AbstractBackgroundColorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes.Materials and methodsWe examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.ResultsMost of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers.ConclusionsColonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.
@article{Mller2024Incidences,
author = {M\o{}ller, P{\r a}l and Haupt, Saskia and Ahadova, Aysel and Kloor, Matthias and Sampson, Julian R. and Sunde, Lone and Sepp{\" a}l{\" a}, Toni and Burn, John and Bernstein, Inge and Capella, Gabriel and Evans, D. Gareth and Lindblom, Annika and Winship, Ingrid and Macrae, Finlay and Katz, Lior and Laish, Ido and Vainer, Elez and Monahan, Kevin and Half, Elizabeth and Horisberger, Karoline and da Silva, Leandro Apolin{\' a}rio and Heuveline, Vincent and Therkildsen, Christina and Lautrup, Charlotte and Klarskov, Louise L and Cavestro, Giulia Martina and M{\" o}slein, Gabriela and Hovig, Eivind and Dominguez-Valentin, Mev},
journal = {Hereditary Cancer in Clinical Practice},
number = {1},
year = {2024},
month = {may 13},
publisher = {{Springer Science and Business Media LLC}},
title = {Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated ``{Big} {Bang}'' pathway to {CRC} in three of the four {Lynch} syndromes},
volume = {22},
}
@article{Mller2024Incidences,
abstract = {\textless{}jats:title\textgreater{}Abstract\textless{}/jats:title\textgreater{}\textless{}jats:sec\textgreater{}
\textless{}jats:title\textgreater{}Background\textless{}/jats:title\textgreater{}
\textless{}jats:p\textgreater{}Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (\textless{}jats:italic\textgreater{}path\textunderscore{}MMR\textless{}/jats:italic\textgreater{}) genes.\textless{}/jats:p\textgreater{}
\textless{}/jats:sec\textgreater{}\textless{}jats:sec\textgreater{}
\textless{}jats:title\textgreater{}Materials and methods\textless{}/jats:title\textgreater{}
\textless{}jats:p\textgreater{}We examined the CRC and colorectal adenoma incidences in 3,574 \textless{}jats:italic\textgreater{}path\textunderscore{}MLH1, path\textunderscore{}MSH2, path\textunderscore{}MSH6\textless{}/jats:italic\textgreater{} and \textless{}jats:italic\textgreater{}path\textunderscore{}PMS2\textless{}/jats:italic\textgreater{} carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.\textless{}/jats:p\textgreater{}
\textless{}/jats:sec\textgreater{}\textless{}jats:sec\textgreater{}
\textless{}jats:title\textgreater{}Results\textless{}/jats:title\textgreater{}
\textless{}jats:p\textgreater{}Most of the \textless{}jats:italic\textgreater{}path\textunderscore{}MMR\textless{}/jats:italic\textgreater{} carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in \textless{}jats:italic\textgreater{}path\textunderscore{}PMS2\textless{}/jats:italic\textgreater{} carriers.\textless{}/jats:p\textgreater{}
\textless{}/jats:sec\textgreater{}\textless{}jats:sec\textgreater{}
\textless{}jats:title\textgreater{}Conclusions\textless{}/jats:title\textgreater{}
\textless{}jats:p\textgreater{}Colonoscopy prevented CRC in \textless{}jats:italic\textgreater{}path\textunderscore{}PMS2\textless{}/jats:italic\textgreater{} carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.\textless{}/jats:p\textgreater{}
\textless{}/jats:sec\textgreater{}},
author = {M\o{}ller, P{\r a}l and Haupt, Saskia and Ahadova, Aysel and Kloor, Matthias and Sampson, Julian R. and Sunde, Lone and Sepp{\" a}l{\" a}, Toni and Burn, John and Bernstein, Inge and Capella, Gabriel and Evans, D. Gareth and Lindblom, Annika and Winship, Ingrid and Macrae, Finlay and Katz, Lior and Laish, Ido and Vainer, Elez and Monahan, Kevin and Half, Elizabeth and Horisberger, Karoline and da Silva, Leandro Apolin{\' a}rio and Heuveline, Vincent and Therkildsen, Christina and Lautrup, Charlotte and Klarskov, Louise L and Cavestro, Giulia Martina and M{\" o}slein, Gabriela and Hovig, Eivind and Dominguez-Valentin, Mev},
journaltitle = {Hereditary Cancer in Clinical Practice},
shortjournal = {Hered Cancer Clin Pract},
doi = {10.1186/s13053-024-00279-3},
issn = {1897-4287},
number = {1},
date = {2024-05-13},
language = {en},
publisher = {{Springer Science and Business Media LLC}},
title = {Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated ``{Big} {Bang}'' pathway to {CRC} in three of the four {Lynch} syndromes},
url = {http://dx.doi.org/10.1186/s13053-024-00279-3},
volume = {22},
}
In medical applications, artificial intelligence (AI) methods have achieved considerable progress in various areas and also in newborn screening programs. In particular, interpretable AI methods have been applied in newborn screening aiming to increase analytical specificity and predictive power of screening results. In this study, we apply ensemble and deep learning methods in newborn screening for isovaleric aciduria (IVA) on a data set containing more than 2 million newborns. We show that these methods can reduce the number of newborns falsely classified with IVA by 100% with Extreme Gradient Boosting (XGBoost), by 78.94% with Random Forest (RF), and by 78.94% with Feed Forward Neural Networks (FFNN) compared to currently applied newborn screening methods. Furthermore, we show how explainable AI (XAI) methods can be used to interpret these black-box classification results and further apply them for potential biomarker discovery. The XAI methods reveal that besides the biomarker isovaleryl carnitine (C5), the birth year and the amino acid tryptophan (Trp) are influential in reducing the false positive rate. By this, we show that ensemble and deep learning could be highly beneficial in newborn screening and could have a major impact on newborns and their families, as it reduces false positive screening results and guides new directions for future research in this field.
@inproceedings{Zaunseder2023Deep,
author = {Zaunseder, Elaine and M{\" u}tze, Ulrike and Garbade, Sven F. and Haupt, Saskia and K{\" o}lker, Stefan and Heuveline, Vincent},
booktitle = {2023 {IEEE} {Symposium} {Series} on {Computational} {Intelligence} ({SSCI})},
year = {2023},
month = {dec 5},
organization = {IEEE},
title = {Deep {Learning} and {Explainable} {Artificial} {Intelligence} for {Improving} {Specificity} and {Detecting} {Metabolic} {Patterns} in {Newborn} {Screening}},
}
@inproceedings{Zaunseder2023Deep,
abstract = {In medical applications, artificial intelligence (AI) methods have achieved considerable progress in various areas and also in newborn screening programs. In particular, interpretable AI methods have been applied in newborn screening aiming to increase analytical specificity and predictive power of screening results. In this study, we apply ensemble and deep learning methods in newborn screening for isovaleric aciduria (IVA) on a data set containing more than 2 million newborns. We show that these methods can reduce the number of newborns falsely classified with IVA by 100% with Extreme Gradient Boosting (XGBoost), by 78.94% with Random Forest (RF), and by 78.94% with Feed Forward Neural Networks (FFNN) compared to currently applied newborn screening methods. Furthermore, we show how explainable AI (XAI) methods can be used to interpret these black-box classification results and further apply them for potential biomarker discovery. The XAI methods reveal that besides the biomarker isovaleryl carnitine (C5), the birth year and the amino acid tryptophan (Trp) are influential in reducing the false positive rate. By this, we show that ensemble and deep learning could be highly beneficial in newborn screening and could have a major impact on newborns and their families, as it reduces false positive screening results and guides new directions for future research in this field.},
author = {Zaunseder, Elaine and M{\" u}tze, Ulrike and Garbade, Sven F. and Haupt, Saskia and K{\" o}lker, Stefan and Heuveline, Vincent},
booktitle = {2023 {IEEE} {Symposium} {Series} on {Computational} {Intelligence} ({SSCI})},
doi = {10.1109/ssci52147.2023.10371991},
eventtitle = {2023 {IEEE} {Symposium} {Series} on {Computational} {Intelligence} ({SSCI})},
date = {2023-12-05},
publisher = {IEEE},
title = {Deep {Learning} and {Explainable} {Artificial} {Intelligence} for {Improving} {Specificity} and {Detecting} {Metabolic} {Patterns} in {Newborn} {Screening}},
url = {http://dx.doi.org/10.1109/SSCI52147.2023.10371991},
}
P. MĂžller, T. SeppĂ€lĂ€, A. Ahadova, E. Crosbie, E. Holinski-Feder, R. Scott, S. Haupt, G. Möslein, I. Winship, S. Broeke, K. Kohut, N. Ryan, P. Bauerfeind, L. Thomas, D. Evans, S. Aretz, R. Sijmons, E. Half, K. Heinimann, K. Horisberger, K. Monahan, C. Engel, G. Cavestro, R. Fruscio, N. Abu-Freha, L. Zohar, L. Laghi, L. Bertario, B. Bonanni, M. Tibiletti, L. Lino-Silva, C. Vaccaro, A. Valle, B. Rossi, L. da Silva, I. de Oliveira Nascimento, N. Rossi, T. DÄbniak, J. Mecklin, I. Bernstein, A. Lindblom, L. Sunde, S. Nakken, V. Heuveline, J. Burn, E. Hovig, M. Kloor, J. Sampson, M. Dominguez-Valentin, On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org): Dominantly inherited micro-satellite instable cancer â the four Lynch syndromes - an EHTG, PLSD position statement. Hereditary Cancer in Clinical Practice, October 2023 DOI: 10.1186/s13053-023-00263-3
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an âaverage sex âor a pathogenic variant in an âaverage Lynch syndrome geneâ and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the hostâs adaptive immune systemâs ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune systemâs capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
@article{Mller2023Dominantly,
author = {M\o{}ller, Pal and Sepp{\" a}l{\" a}, Toni T. and Ahadova, Aysel and Crosbie, Emma J. and Holinski-Feder, Elke and Scott, Rodney and Haupt, Saskia and M{\" o}slein, Gabriela and Winship, Ingrid and Broeke, Sanne W. Bajwa-ten and Kohut, Kelly E. and Ryan, Neil and Bauerfeind, Peter and Thomas, Laura E. and Evans, D. Gareth and Aretz, Stefan and Sijmons, Rolf H. and Half, Elizabeth and Heinimann, Karl and Horisberger, Karoline and Monahan, Kevin and Engel, Christoph and Cavestro, Giulia Martina and Fruscio, Robert and Abu-Freha, Naim and Zohar, Levi and Laghi, Luigi and Bertario, Lucio and Bonanni, Bernardo and Tibiletti, Maria Grazia and Lino-Silva, Leonardo S. and Vaccaro, Carlos and Valle, Adriana Della and Rossi, Benedito Mauro and da Silva, Leandro Apolin{\' a}rio and de Oliveira Nascimento, Ivana Lucia and Rossi, Norma Teresa and D{\k e}bniak, Tadeusz and Mecklin, Jukka-Pekka and Bernstein, Inge and Lindblom, Annika and Sunde, Lone and Nakken, Sigve and Heuveline, Vincent and Burn, John and Hovig, Eivind and Kloor, Matthias and Sampson, Julian R. and Dominguez-Valentin, Mev},
journal = {Hereditary Cancer in Clinical Practice},
number = {1},
year = {2023},
month = {oct 11},
publisher = {{Springer Science and Business Media LLC}},
title = {Dominantly inherited micro-satellite instable cancer -- the four {Lynch} syndromes - an {EHTG}, {PLSD} position statement},
volume = {21},
}
@article{Mller2023Dominantly,
abstract = {The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes \textit{MSH2, MLH1, MSH6} and \textit{PMS2} has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an ``average sex ``or a pathogenic variant in an ``average Lynch syndrome gene'' and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host\textquoteright{}s adaptive immune system\textquoteright{}s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system\textquoteright{}s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.},
author = {M\o{}ller, Pal and Sepp{\" a}l{\" a}, Toni T. and Ahadova, Aysel and Crosbie, Emma J. and Holinski-Feder, Elke and Scott, Rodney and Haupt, Saskia and M{\" o}slein, Gabriela and Winship, Ingrid and Broeke, Sanne W. Bajwa-ten and Kohut, Kelly E. and Ryan, Neil and Bauerfeind, Peter and Thomas, Laura E. and Evans, D. Gareth and Aretz, Stefan and Sijmons, Rolf H. and Half, Elizabeth and Heinimann, Karl and Horisberger, Karoline and Monahan, Kevin and Engel, Christoph and Cavestro, Giulia Martina and Fruscio, Robert and Abu-Freha, Naim and Zohar, Levi and Laghi, Luigi and Bertario, Lucio and Bonanni, Bernardo and Tibiletti, Maria Grazia and Lino-Silva, Leonardo S. and Vaccaro, Carlos and Valle, Adriana Della and Rossi, Benedito Mauro and da Silva, Leandro Apolin{\' a}rio and de Oliveira Nascimento, Ivana Lucia and Rossi, Norma Teresa and D{\k e}bniak, Tadeusz and Mecklin, Jukka-Pekka and Bernstein, Inge and Lindblom, Annika and Sunde, Lone and Nakken, Sigve and Heuveline, Vincent and Burn, John and Hovig, Eivind and Kloor, Matthias and Sampson, Julian R. and Dominguez-Valentin, Mev},
journaltitle = {Hereditary Cancer in Clinical Practice},
shortjournal = {Hered Cancer Clin Pract},
doi = {10.1186/s13053-023-00263-3},
issn = {1897-4287},
number = {1},
date = {2023-10-11},
language = {en},
publisher = {{Springer Science and Business Media LLC}},
title = {Dominantly inherited micro-satellite instable cancer -- the four {Lynch} syndromes - an {EHTG}, {PLSD} position statement},
url = {http://dx.doi.org/10.1186/s13053-023-00263-3},
volume = {21},
}
Cancer is one of the leading causes of disease-related death worldwide. In recent years, large amounts of data on cancer genetics and molecular characteristics have become available and accumulated with increasing speed. However, the current understanding of cancer as a disease is still limited by the lack of suitable models that allow interpreting these data in proper ways. Thus, the highly interdisciplinary research field of mathematical oncology has evolved to use mathematics, modeling, and simulations to study cancer with the overall goal to improve clinical patient care. This dissertation aims at developing mathematical models and tools for different spatial scales of cancer development at the example of colorectal cancer in Lynch syndrome, the most common inherited colorectal cancer predisposition syndrome. We derive model-driven approaches for carcinogenesis at the DNA, cell, and crypt level, as well as data-driven methods for cancer-immune interactions at the DNA level and for the evaluation of diagnostic procedures at the Lynch syndrome population level. The developed models present an important step toward an improved understanding of hereditary cancer as a disease aiming at rapid implementation into clinical management guidelines and into the development of novel, innovative approaches for prevention and treatment.
@misc{Haupt2023Mathematical,
author = {Haupt, Saskia},
year = {2023},
month = {apr 19},
school = {Heidelberg University Library},
title = {Mathematical modeling of {Lynch} syndrome carcinogenesis},
}
@thesis{Haupt2023Mathematical,
abstract = {\textless{}jats:p\textgreater{} Cancer is one of the leading causes of disease-related death worldwide. In recent years, large amounts of data on cancer genetics and molecular characteristics have become available and accumulated with increasing speed. However, the current understanding of cancer as a disease is still limited by the lack of suitable models that allow interpreting these data in proper ways. Thus, the highly interdisciplinary research field of mathematical oncology has evolved to use mathematics, modeling, and simulations to study cancer with the overall goal to improve clinical patient care. This dissertation aims at developing mathematical models and tools for different spatial scales of cancer development at the example of colorectal cancer in Lynch syndrome, the most common inherited colorectal cancer predisposition syndrome. We derive model-driven approaches for carcinogenesis at the DNA, cell, and crypt level, as well as data-driven methods for cancer-immune interactions at the DNA level and for the evaluation of diagnostic procedures at the Lynch syndrome population level. The developed models present an important step toward an improved understanding of hereditary cancer as a disease aiming at rapid implementation into clinical management guidelines and into the development of novel, innovative approaches for prevention and treatment.\textless{}/jats:p\textgreater{}},
author = {Haupt, Saskia},
booktitle = {Heidelberg {University} {Library}},
doi = {10.11588/HEIDOK.00033194},
date = {2023-04-19},
institution = {Heidelberg University Library},
title = {Mathematical modeling of {Lynch} syndrome carcinogenesis},
url = {https://archiv.ub.uni-heidelberg.de/volltextserver/id/eprint/33194},
}
M. Dominguez-Valentin, S. Haupt, T. SeppĂ€lĂ€, J. Sampson, L. Sunde, I. Bernstein, M. Jenkins, C. Engel, S. Aretz, M. Nielsen, G. Capella, F. Balaguer, D. Evans, J. Burn, E. Holinski-Feder, L. Bertario, B. Bonanni, A. Lindblom, Z. Levi, F. Macrae, I. Winship, J. Plazzer, R. Sijmons, L. Laghi, A. Della Valle, K. Heinimann, T. DÄbniak, R. Fruscio, F. Lopez-Koestner, K. Alvarez-Valenzuela, L. Katz, I. Laish, E. Vainer, C. Vaccaro, D. Carraro, K. Monahan, E. Half, A. Stakelum, D. Winter, R. Kennelly, N. Gluck, H. Sheth, N. Abu-Freha, M. Greenblatt, B. Rossi, M. Bohorquez, G. Cavestro, L. Lino-Silva, K. Horisberger, M. Tibiletti, I. Nascimento, H. Thomas, N. Rossi, L. ApolinĂĄrio da Silva, A. ZarĂĄnd, J. Ruiz-Bañobre, V. Heuveline, J. Mecklin, K. PylvĂ€nĂ€inen, L. Renkonen-Sinisalo, A. Lepistö, P. PeltomĂ€ki, C. Therkildsen, M. Madsen, S. Burgdorf, J. Hopper, A. Win, R. Haile, N. Lindor, S. Gallinger, L. Le Marchand, P. Newcomb, J. Figueiredo, D. Buchanan, S. Thibodeau, M. von Knebel Doeberitz, M. Loeffler, N. Rahner, E. Schröck, V. Steinke-Lange, W. Schmiegel, D. Vangala, C. Perne, R. HĂŒneburg, S. Redler, R. BĂŒttner, J. Weitz, M. Pineda, N. Duenas, J. Vidal, L. Moreira, A. SĂĄnchez, E. Hovig, S. Nakken, K. Green, F. Lalloo, J. Hill, E. Crosbie, M. Mints, Y. Goldberg, D. Tjandra, S. ten Broeke, R. Kariv, G. Rosner, S. Advani, L. Thomas, P. Shah, M. Shah, F. Neffa, P. Esperon, W. Pavicic, G. Torrezan, T. Bassaneze, C. Martin, G. Moslein, P. Moller: Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database. eClinicalMedicine, March 2023 DOI: 10.1016/j.eclinm.2023.101909
@article{Dominguez2023Mortality,
author = {Dominguez-Valentin, Mev and Haupt, Saskia and Sepp{\" a}l{\" a}, Toni T. and Sampson, Julian R. and Sunde, Lone and Bernstein, Inge and Jenkins, Mark A. and Engel, Christoph and Aretz, Stefan and Nielsen, Maartje and Capella, Gabriel and Balaguer, Francesc and Evans, Dafydd Gareth and Burn, John and Holinski-Feder, Elke and Bertario, Lucio and Bonanni, Bernardo and Lindblom, Annika and Levi, Zohar and Macrae, Finlay and Winship, Ingrid and Plazzer, John-Paul and Sijmons, Rolf and Laghi, Luigi and Della Valle, Adriana and Heinimann, Karl and D{\k e}bniak, Tadeusz and Fruscio, Robert and Lopez-Koestner, Francisco and Alvarez-Valenzuela, Karin and Katz, Lior H. and Laish, Ido and Vainer, Elez and Vaccaro, Carlos and Carraro, Dirce Maria and Monahan, Kevin and Half, Elizabeth and Stakelum, Aine and Winter, Des and Kennelly, Rory and Gluck, Nathan and Sheth, Harsh and Abu-Freha, Naim and Greenblatt, Marc and Rossi, Benedito Mauro and Bohorquez, Mabel and Cavestro, Giulia Martina and Lino-Silva, Leonardo S. and Horisberger, Karoline and Tibiletti, Maria Grazia and Nascimento, Ivana do and Thomas, Huw and Rossi, Norma Teresa and Apolin{\' a}rio da Silva, Leandro and Zar{\' a}nd, Attila and Ruiz-Ba{\~ n}obre, Juan and Heuveline, Vincent and Mecklin, Jukka-Pekka and Pylv{\" a}n{\" a}inen, Kirsi and Renkonen-Sinisalo, Laura and Lepist{\" o}, Anna and Peltom{\" a}ki, P{\" a}ivi and Therkildsen, Christina and Madsen, Mia Gebauer and Burgdorf, Stefan Kobbelgaard and Hopper, John L. and Win, Aung Ko and Haile, Robert W. and Lindor, Noralane and Gallinger, Steven and Le Marchand, Lo{\" i}c and Newcomb, Polly A. and Figueiredo, Jane and Buchanan, Daniel D. and Thibodeau, Stephen N. and von Knebel Doeberitz, Magnus and Loeffler, Markus and Rahner, Nils and Schr{\" o}ck, Evelin and Steinke-Lange, Verena and Schmiegel, Wolff and Vangala, Deepak and Perne, Claudia and H{\" u}neburg, Robert and Redler, Silke and B{\" u}ttner, Reinhard and Weitz, J{\" u}rgen and Pineda, Marta and Duenas, Nuria and Vidal, Joan Brunet and Moreira, Leticia and S{\' a}nchez, Ariadna and Hovig, Eivind and Nakken, Sigve and Green, Kate and Lalloo, Fiona and Hill, James and Crosbie, Emma and Mints, Miriam and Goldberg, Yael and Tjandra, Douglas and ten Broeke, Sanne W. and Kariv, Revital and Rosner, Guy and Advani, Suresh H. and Thomas, Lidiya and Shah, Pankaj and Shah, Mithun and Neffa, Florencia and Esperon, Patricia and Pavicic, Walter and Torrezan, Giovana Tardin and Bassaneze, Thiago and Martin, Claudia Alejandra and Moslein, Gabriela and Moller, P{\r a}l},
journal = {eClinicalMedicine},
year = {2023},
month = {mar 21},
pages = {101909},
publisher = {Elsevier BV},
title = {Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective {Lynch} syndrome database},
}
@article{Dominguez2023Mortality,
author = {Dominguez-Valentin, Mev and Haupt, Saskia and Sepp{\" a}l{\" a}, Toni T. and Sampson, Julian R. and Sunde, Lone and Bernstein, Inge and Jenkins, Mark A. and Engel, Christoph and Aretz, Stefan and Nielsen, Maartje and Capella, Gabriel and Balaguer, Francesc and Evans, Dafydd Gareth and Burn, John and Holinski-Feder, Elke and Bertario, Lucio and Bonanni, Bernardo and Lindblom, Annika and Levi, Zohar and Macrae, Finlay and Winship, Ingrid and Plazzer, John-Paul and Sijmons, Rolf and Laghi, Luigi and Della Valle, Adriana and Heinimann, Karl and D{\k e}bniak, Tadeusz and Fruscio, Robert and Lopez-Koestner, Francisco and Alvarez-Valenzuela, Karin and Katz, Lior H. and Laish, Ido and Vainer, Elez and Vaccaro, Carlos and Carraro, Dirce Maria and Monahan, Kevin and Half, Elizabeth and Stakelum, Aine and Winter, Des and Kennelly, Rory and Gluck, Nathan and Sheth, Harsh and Abu-Freha, Naim and Greenblatt, Marc and Rossi, Benedito Mauro and Bohorquez, Mabel and Cavestro, Giulia Martina and Lino-Silva, Leonardo S. and Horisberger, Karoline and Tibiletti, Maria Grazia and Nascimento, Ivana do and Thomas, Huw and Rossi, Norma Teresa and Apolin{\' a}rio da Silva, Leandro and Zar{\' a}nd, Attila and Ruiz-Ba{\~ n}obre, Juan and Heuveline, Vincent and Mecklin, Jukka-Pekka and Pylv{\" a}n{\" a}inen, Kirsi and Renkonen-Sinisalo, Laura and Lepist{\" o}, Anna and Peltom{\" a}ki, P{\" a}ivi and Therkildsen, Christina and Madsen, Mia Gebauer and Burgdorf, Stefan Kobbelgaard and Hopper, John L. and Win, Aung Ko and Haile, Robert W. and Lindor, Noralane and Gallinger, Steven and Le Marchand, Lo{\" i}c and Newcomb, Polly A. and Figueiredo, Jane and Buchanan, Daniel D. and Thibodeau, Stephen N. and von Knebel Doeberitz, Magnus and Loeffler, Markus and Rahner, Nils and Schr{\" o}ck, Evelin and Steinke-Lange, Verena and Schmiegel, Wolff and Vangala, Deepak and Perne, Claudia and H{\" u}neburg, Robert and Redler, Silke and B{\" u}ttner, Reinhard and Weitz, J{\" u}rgen and Pineda, Marta and Duenas, Nuria and Vidal, Joan Brunet and Moreira, Leticia and S{\' a}nchez, Ariadna and Hovig, Eivind and Nakken, Sigve and Green, Kate and Lalloo, Fiona and Hill, James and Crosbie, Emma and Mints, Miriam and Goldberg, Yael and Tjandra, Douglas and ten Broeke, Sanne W. and Kariv, Revital and Rosner, Guy and Advani, Suresh H. and Thomas, Lidiya and Shah, Pankaj and Shah, Mithun and Neffa, Florencia and Esperon, Patricia and Pavicic, Walter and Torrezan, Giovana Tardin and Bassaneze, Thiago and Martin, Claudia Alejandra and Moslein, Gabriela and Moller, P{\r a}l},
journaltitle = {eClinicalMedicine},
shortjournal = {eClinicalMedicine},
doi = {10.1016/j.eclinm.2023.101909},
issn = {2589-5370},
date = {2023-03-21},
language = {en},
pages = {101909},
publisher = {Elsevier BV},
title = {Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective {Lynch} syndrome database},
url = {http://dx.doi.org/10.1016/j.eclinm.2023.101909},
}
@article{Ahadova2023two,
author = {Ahadova, Aysel and Stenzinger, Albrecht and Sepp{\" a}l{\" a}, Toni and H{\" u}neburg, Robert and Kloor, Matthias and Bl{\" a}ker, Hendrik and Wittemann, Jan-Niklas and Endris, Volker and Gerling, Leonie and Bertram, Veit and Neumuth, Marie Theres and Witt, Johannes and Graf, Sebastian and Kristiansen, Glen and Hommerding, Oliver and Haupt, Saskia and Zeilmann, Alexander and Heuveline, Vincent and Kazdal, Daniel and Gebert, Johannes and von Knebel Doeberitz, Magnus and Mecklin, Jukka-Pekka and Nattermann, Jacob},
journal = {Gastroenterology},
year = {2023},
month = {mar 15},
publisher = {Elsevier BV},
title = {A ``two-in-one hit'' model of shortcut carcinogenesis in {MLH1} {Lynch} syndrome carriers},
}
@article{Ahadova2023two,
author = {Ahadova, Aysel and Stenzinger, Albrecht and Sepp{\" a}l{\" a}, Toni and H{\" u}neburg, Robert and Kloor, Matthias and Bl{\" a}ker, Hendrik and Wittemann, Jan-Niklas and Endris, Volker and Gerling, Leonie and Bertram, Veit and Neumuth, Marie Theres and Witt, Johannes and Graf, Sebastian and Kristiansen, Glen and Hommerding, Oliver and Haupt, Saskia and Zeilmann, Alexander and Heuveline, Vincent and Kazdal, Daniel and Gebert, Johannes and von Knebel Doeberitz, Magnus and Mecklin, Jukka-Pekka and Nattermann, Jacob},
journaltitle = {Gastroenterology},
shortjournal = {Gastroenterology},
doi = {10.1053/j.gastro.2023.03.007},
issn = {0016-5085},
date = {2023-03-15},
language = {en},
publisher = {Elsevier BV},
title = {A ``two-in-one hit'' model of shortcut carcinogenesis in {MLH1} {Lynch} syndrome carriers},
url = {http://dx.doi.org/10.1053/j.gastro.2023.03.007},
}
Isovaleric aciduria (IVA) is a rare disorder of leucine metabolism and part of newborn screening (NBS) programs worldwide. However, NBS for IVA is hampered by, first, the increased birth prevalence due to the identification of individuals with an attenuated disease variant (so-called âmildâ IVA) and, second, an increasing number of false positive screening results due to the use of pivmecillinam contained in the medication. Recently, machine learning (ML) methods have been analyzed, analogous to new biomarkers or second-tier methods, in the context of NBS. In this study, we investigated the application of machine learning classification methods to improve IVA classification using an NBS data set containing 2,106,090 newborns screened in Heidelberg, Germany. Therefore, we propose to combine two methods, linear discriminant analysis, and ridge logistic regression as an additional step, a digital-tier, to traditional NBS. Our results show that this reduces the false positive rate by 69.9% from 103 to 31 while maintaining 100% sensitivity in cross-validation. The ML methods were able to classify mild and classic IVA from normal newborns solely based on the NBS data and revealed that besides isovalerylcarnitine (C5), the metabolite concentration of tryptophan (Trp) is important for improved classification. Overall, applying ML methods to improve the specificity of IVA could have a major impact on newborns, as it could reduce the newbornsâ and familiesâ burden of false positives or over-treatment.
@article{Zaunseder2023Machine,
author = {Zaunseder, Elaine and M{\" u}tze, Ulrike and Garbade, Sven F. and Haupt, Saskia and Feyh, Patrik and Hoffmann, Georg F. and Heuveline, Vincent and K{\" o}lker, Stefan},
journal = {Metabolites},
number = {2},
year = {2023},
month = {feb 18},
pages = {304},
publisher = {MDPI AG},
title = {Machine {Learning} {Methods} {Improve} {Specificity} in {Newborn} {Screening} for {Isovaleric} {Aciduria}},
volume = {13},
}
@article{Zaunseder2023Machine,
abstract = {\textless{}jats:p\textgreater{}Isovaleric aciduria (IVA) is a rare disorder of leucine metabolism and part of newborn screening (NBS) programs worldwide. However, NBS for IVA is hampered by, first, the increased birth prevalence due to the identification of individuals with an attenuated disease variant (so-called ``mild'' IVA) and, second, an increasing number of false positive screening results due to the use of pivmecillinam contained in the medication. Recently, machine learning (ML) methods have been analyzed, analogous to new biomarkers or second-tier methods, in the context of NBS. In this study, we investigated the application of machine learning classification methods to improve IVA classification using an NBS data set containing 2,106,090 newborns screened in Heidelberg, Germany. Therefore, we propose to combine two methods, linear discriminant analysis, and ridge logistic regression as an additional step, a digital-tier, to traditional NBS. Our results show that this reduces the false positive rate by 69.9% from 103 to 31 while maintaining 100% sensitivity in cross-validation. The ML methods were able to classify mild and classic IVA from normal newborns solely based on the NBS data and revealed that besides isovalerylcarnitine (C5), the metabolite concentration of tryptophan (Trp) is important for improved classification. Overall, applying ML methods to improve the specificity of IVA could have a major impact on newborns, as it could reduce the newborns\textquoteright{} and families\textquoteright{} burden of false positives or over-treatment.\textless{}/jats:p\textgreater{}},
author = {Zaunseder, Elaine and M{\" u}tze, Ulrike and Garbade, Sven F. and Haupt, Saskia and Feyh, Patrik and Hoffmann, Georg F. and Heuveline, Vincent and K{\" o}lker, Stefan},
journaltitle = {Metabolites},
shortjournal = {Metabolites},
doi = {10.3390/metabo13020304},
issn = {2218-1989},
number = {2},
date = {2023-02-18},
language = {en},
pages = {304},
publisher = {MDPI AG},
title = {Machine {Learning} {Methods} {Improve} {Specificity} in {Newborn} {Screening} for {Isovaleric} {Aciduria}},
url = {http://dx.doi.org/10.3390/metabo13020304},
volume = {13},
}
The HLA system represents a central component of the antigen presentation machinery. As every patient possesses a defined set of HLA molecules, only certain antigens can be presented on the cell surface. Thus, studying HLA type-dependent antigen presentation can improve the understanding of variation in susceptibility to various diseases, including infectious diseases and cancer. In archival formalin-fixed paraffin-embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of HLA-A*02, the most common HLA-A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS-based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of HLA-A*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%â100% and 91.19%â100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite-unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying HLA-A*02 alleles.
@article{Witt2022simple,
author = {Witt, Johannes and Haupt, Saskia and Ahadova, Aysel and Bohaumilitzky, Lena and Fuchs, Vera and Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Sepp{\" a}l{\" a}, Toni T. and F{\" u}rst, Daniel and Walle, Thomas and Busch, Elena and Haag, Georg Martin and H{\" u}neburg, Robert and Nattermann, Jacob and von Knebel Doeberitz, Magnus and Heuveline, Vincent and Kloor, Matthias},
journal = {HLA},
year = {2022},
month = {oct 25},
publisher = {Wiley},
title = {A simple approach for detecting
\textit{{HLAA}}
*02 alleles in archival formalinfixed paraffinembedded tissue samples and an application example for studying cancer immunoediting},
}
@article{Witt2022simple,
abstract = {The HLA system represents a central component of the antigen presentation machinery. As every patient possesses a defined set of HLA molecules, only certain antigens can be presented on the cell surface. Thus, studying HLA type-dependent antigen presentation can improve the understanding of variation in susceptibility to various diseases, including infectious diseases and cancer. In archival formalin-fixed paraffin-embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of \textit{HLA-A}*02, the most common HLA-A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS-based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of \textit{HLA-A}*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%--100% and 91.19%--100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite-unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying \textit{HLA-A}*02 alleles.},
author = {Witt, Johannes and Haupt, Saskia and Ahadova, Aysel and Bohaumilitzky, Lena and Fuchs, Vera and Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Sepp{\" a}l{\" a}, Toni T. and F{\" u}rst, Daniel and Walle, Thomas and Busch, Elena and Haag, Georg Martin and H{\" u}neburg, Robert and Nattermann, Jacob and von Knebel Doeberitz, Magnus and Heuveline, Vincent and Kloor, Matthias},
journaltitle = {HLA},
shortjournal = {HLA},
doi = {10.1111/tan.14846},
issn = {2059-2302},
date = {2022-10-25},
language = {en},
publisher = {Wiley},
title = {A simple approach for detecting
\textit{{HLAA}}
*02 alleles in archival formalinfixed paraffinembedded tissue samples and an application example for studying cancer immunoediting},
url = {http://dx.doi.org/10.1111/tan.14846},
}
A. Ahadova, J. Witt, S. Haupt, R. Gallon, R. HĂŒneburg, J. Nattermann, S. ten Broeke, L. Bohaumilitzky, A. HernandezâSanchez, M. SantibanezâKoref, M. Jackson, M. Ahtiainen, K. PylvĂ€nĂ€inen, K. Andini, V. Grolmusz, G. Möslein, M. DominguezâValentin, P. MĂžller, D. FĂŒrst, R. Sijmons, G. Borthwick, J. Burn, J. Mecklin, V. Heuveline, M. von Knebel Doeberitz, T. SeppĂ€lĂ€, M. Kloor: Is
HLA
type a possible cancer risk modifier in Lynch syndrome?. International Journal of Cancer, October 2022 DOI: 10.1002/ijc.34312
Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.
Scientific hypothesis of the INDICATE collaborative initiative
INDICATE aims to find out, whether the risk of developing a tumor in LS is associated with the HLA type of the individual, so delineating the HLA type-related cancer risk of LS carriers.
@article{Ahadova2022Is,
author = {Ahadova, Aysel and Witt, Johannes and Haupt, Saskia and Gallon, Richard and H{\" u}neburg, Robert and Nattermann, Jacob and ten Broeke, Sanne and Bohaumilitzky, Lena and HernandezSanchez, Alejandro and SantibanezKoref, Mauro and Jackson, Michael S. and Ahtiainen, Maarit and Pylv{\" a}n{\" a}inen, Kirsi and Andini, Katarina and Grolmusz, Vince Kornel and M{\" o}slein, Gabriela and DominguezValentin, Mev and M\o{}ller, P{\r a}l and F{\" u}rst, Daniel and Sijmons, Rolf and Borthwick, Gillian M. and Burn, John and Mecklin, JukkaPekka and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Sepp{\" a}l{\" a}, Toni and Kloor, Matthias},
journal = {International Journal of Cancer},
year = {2022},
month = {oct 14},
publisher = {Wiley},
title = {Is
\textless{}scp\textgreater{}{HLA}\textless{}/scp\textgreater{}
type a possible cancer risk modifier in {Lynch} syndrome?},
}
@article{Ahadova2022Is,
abstract = {Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.},
author = {Ahadova, Aysel and Witt, Johannes and Haupt, Saskia and Gallon, Richard and H{\" u}neburg, Robert and Nattermann, Jacob and ten Broeke, Sanne and Bohaumilitzky, Lena and HernandezSanchez, Alejandro and SantibanezKoref, Mauro and Jackson, Michael S. and Ahtiainen, Maarit and Pylv{\" a}n{\" a}inen, Kirsi and Andini, Katarina and Grolmusz, Vince Kornel and M{\" o}slein, Gabriela and DominguezValentin, Mev and M\o{}ller, P{\r a}l and F{\" u}rst, Daniel and Sijmons, Rolf and Borthwick, Gillian M. and Burn, John and Mecklin, JukkaPekka and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Sepp{\" a}l{\" a}, Toni and Kloor, Matthias},
journaltitle = {International Journal of Cancer},
shortjournal = {Intl Journal of Cancer},
doi = {10.1002/ijc.34312},
issn = {0020-7136},
date = {2022-10-14},
language = {en},
publisher = {Wiley},
title = {Is
\textless{}scp\textgreater{}{HLA}\textless{}/scp\textgreater{}
type a possible cancer risk modifier in {Lynch} syndrome?},
url = {http://dx.doi.org/10.1002/ijc.34312},
}
Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
@article{Mller2022Colorectal,
author = {M\o{}ller, P{\r a}l and Sepp{\" a}l{\" a}, Toni and Dowty, James G. and Haupt, Saskia and Dominguez-Valentin, Mev and Sunde, Lone and Bernstein, Inge and Engel, Christoph and Aretz, Stefan and Nielsen, Maartje and Capella, Gabriel and Evans, Dafydd Gareth and Burn, John and Holinski-Feder, Elke and Bertario, Lucio and Bonanni, Bernardo and Lindblom, Annika and Levi, Zohar and Macrae, Finlay and Winship, Ingrid and Plazzer, John-Paul and Sijmons, Rolf and Laghi, Luigi and Valle, Adriana Della and Heinimann, Karl and Half, Elizabeth and Lopez-Koestner, Francisco and Alvarez-Valenzuela, Karin and Scott, Rodney J. and Katz, Lior and Laish, Ido and Vainer, Elez and Vaccaro, Carlos Alberto and Carraro, Dirce Maria and Gluck, Nathan and Abu-Freha, Naim and Stakelum, Aine and Kennelly, Rory and Winter, Des and Rossi, Benedito Mauro and Greenblatt, Marc and Bohorquez, Mabel and Sheth, Harsh and Tibiletti, Maria Grazia and Lino-Silva, Leonardo S. and Horisberger, Karoline and Portenkirchner, Carmen and Nascimento, Ivana and Rossi, Norma Teresa and da Silva, Leandro Apolin{\' a}rio and Thomas, Huw and Zar{\' a}nd, Attila and Mecklin, Jukka-Pekka and Pylv{\" a}n{\" a}inen, Kirsi and Renkonen-Sinisalo, Laura and Lepisto, Anna and Peltom{\" a}ki, P{\" a}ivi and Therkildsen, Christina and Lindberg, Lars Joachim and Thorlacius-Ussing, Ole and von Knebel Doeberitz, Magnus and Loeffler, Markus and Rahner, Nils and Steinke-Lange, Verena and Schmiegel, Wolff and Vangala, Deepak and Perne, Claudia and H{\" u}neburg, Robert and de Vargas, A{\' i}da Falc{\' o}n and Latchford, Andrew and Gerdes, Anne-Marie and Backman, Ann-Sofie and Guill{\' e}n-Ponce, Carmen and Snyder, Carrie and Lautrup, Charlotte K. and Amor, David and Palmero, Edenir and Stoffel, Elena and Duijkers, Floor and Hall, Michael J. and Hampel, Heather and Williams, Heinric and Okkels, Henrik and Lubi{\' n}ski, Jan and Reece, Jeanette and Ngeow, Joanne and Guillem, Jose G. and Arnold, Julie and Wadt, Karin and Monahan, Kevin and Senter, Leigha and Rasmussen, Lene J. and van Hest, Liselotte P. and Ricciardiello, Luigi and Kohonen-Corish, Maija R. J. and Ligtenberg, Marjolijn J. L. and Southey, Melissa and Aronson, Melyssa and Zahary, Mohd N. and Samadder, N. Jewel and Poplawski, Nicola and Hoogerbrugge, Nicoline and Morrison, Patrick J. and James, Paul and Lee, Grant and Chen-Shtoyerman, Rakefet and Ankathil, Ravindran and Pai, Rish and Ward, Robyn and Parry, Susan and D{\k e}bniak, Tadeusz and John, Thomas and van Overeem Hansen, Thomas and Cald{\' e}s, Trinidad and Yamaguchi, Tatsuro and Barca-Tierno, Ver{\' o}nica and Garre, Pilar and Cavestro, Giulia Martina and Weitz, J{\" u}rgen and Redler, Silke and B{\" u}ttner, Reinhard and Heuveline, Vincent and Hopper, John L. and Win, Aung Ko and Lindor, Noralane and Gallinger, Steven and Le Marchand, Lo{\" i}c and Newcomb, Polly A. and Figueiredo, Jane and Buchanan, Daniel D. and Thibodeau, Stephen N. and ten Broeke, Sanne W. and Hovig, Eivind and Nakken, Sigve and Pineda, Marta and Due{\~ n}as, Nuria and Brunet, Joan and Green, Kate and Lalloo, Fiona and Newton, Katie and Crosbie, Emma J. and Mints, Miriam and Tjandra, Douglas and Neffa, Florencia and Esperon, Patricia and Kariv, Revital and Rosner, Guy and Pavicic, Walter Hern{\' a}n and Kalfayan, Pablo and Torrezan, Giovana Tardin and Bassaneze, Thiago and Martin, Claudia and Moslein, Gabriela and Ahadova, Aysel and Kloor, Matthias and Sampson, Julian R. and Jenkins, Mark A.},
journal = {Hereditary Cancer in Clinical Practice},
number = {1},
year = {2022},
month = {oct 1},
publisher = {{Springer Science and Business Media LLC}},
title = {Colorectal cancer incidences in {Lynch} syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium},
volume = {20},
}
@article{Mller2022Colorectal,
abstract = {\textbf{Objective:} To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. \textbf{Methods:} CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (\textit{path\textunderscore{}MMR}) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred \textit{path\textunderscore{}MMR} carriers who were first- or second-degree relatives of Lynch syndrome probands. \textbf{Results:} In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in \textit{path\textunderscore{}MLH1} carriers at 70 years of age were 52% in males and 41% in females; for \textit{path\textunderscore{}MSH2} 50% and 39%; for \textit{path\textunderscore{}MSH6} 13% and 17% and for \textit{path\textunderscore{}PMS2} 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. \textbf{Conclusions:} Prospectively observed CRC incidences (PLSD) in \textit{path\textunderscore{}MLH1} and \textit{path\textunderscore{}MSH2} carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in \textit{path\textunderscore{}MSH6} carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in \textit{path\textunderscore{}PMS2} carriers subjected to colonoscopy, but not significantly so.},
author = {M\o{}ller, P{\r a}l and Sepp{\" a}l{\" a}, Toni and Dowty, James G. and Haupt, Saskia and Dominguez-Valentin, Mev and Sunde, Lone and Bernstein, Inge and Engel, Christoph and Aretz, Stefan and Nielsen, Maartje and Capella, Gabriel and Evans, Dafydd Gareth and Burn, John and Holinski-Feder, Elke and Bertario, Lucio and Bonanni, Bernardo and Lindblom, Annika and Levi, Zohar and Macrae, Finlay and Winship, Ingrid and Plazzer, John-Paul and Sijmons, Rolf and Laghi, Luigi and Valle, Adriana Della and Heinimann, Karl and Half, Elizabeth and Lopez-Koestner, Francisco and Alvarez-Valenzuela, Karin and Scott, Rodney J. and Katz, Lior and Laish, Ido and Vainer, Elez and Vaccaro, Carlos Alberto and Carraro, Dirce Maria and Gluck, Nathan and Abu-Freha, Naim and Stakelum, Aine and Kennelly, Rory and Winter, Des and Rossi, Benedito Mauro and Greenblatt, Marc and Bohorquez, Mabel and Sheth, Harsh and Tibiletti, Maria Grazia and Lino-Silva, Leonardo S. and Horisberger, Karoline and Portenkirchner, Carmen and Nascimento, Ivana and Rossi, Norma Teresa and da Silva, Leandro Apolin{\' a}rio and Thomas, Huw and Zar{\' a}nd, Attila and Mecklin, Jukka-Pekka and Pylv{\" a}n{\" a}inen, Kirsi and Renkonen-Sinisalo, Laura and Lepisto, Anna and Peltom{\" a}ki, P{\" a}ivi and Therkildsen, Christina and Lindberg, Lars Joachim and Thorlacius-Ussing, Ole and von Knebel Doeberitz, Magnus and Loeffler, Markus and Rahner, Nils and Steinke-Lange, Verena and Schmiegel, Wolff and Vangala, Deepak and Perne, Claudia and H{\" u}neburg, Robert and de Vargas, A{\' i}da Falc{\' o}n and Latchford, Andrew and Gerdes, Anne-Marie and Backman, Ann-Sofie and Guill{\' e}n-Ponce, Carmen and Snyder, Carrie and Lautrup, Charlotte K. and Amor, David and Palmero, Edenir and Stoffel, Elena and Duijkers, Floor and Hall, Michael J. and Hampel, Heather and Williams, Heinric and Okkels, Henrik and Lubi{\' n}ski, Jan and Reece, Jeanette and Ngeow, Joanne and Guillem, Jose G. and Arnold, Julie and Wadt, Karin and Monahan, Kevin and Senter, Leigha and Rasmussen, Lene J. and van Hest, Liselotte P. and Ricciardiello, Luigi and Kohonen-Corish, Maija R. J. and Ligtenberg, Marjolijn J. L. and Southey, Melissa and Aronson, Melyssa and Zahary, Mohd N. and Samadder, N. Jewel and Poplawski, Nicola and Hoogerbrugge, Nicoline and Morrison, Patrick J. and James, Paul and Lee, Grant and Chen-Shtoyerman, Rakefet and Ankathil, Ravindran and Pai, Rish and Ward, Robyn and Parry, Susan and D{\k e}bniak, Tadeusz and John, Thomas and van Overeem Hansen, Thomas and Cald{\' e}s, Trinidad and Yamaguchi, Tatsuro and Barca-Tierno, Ver{\' o}nica and Garre, Pilar and Cavestro, Giulia Martina and Weitz, J{\" u}rgen and Redler, Silke and B{\" u}ttner, Reinhard and Heuveline, Vincent and Hopper, John L. and Win, Aung Ko and Lindor, Noralane and Gallinger, Steven and Le Marchand, Lo{\" i}c and Newcomb, Polly A. and Figueiredo, Jane and Buchanan, Daniel D. and Thibodeau, Stephen N. and ten Broeke, Sanne W. and Hovig, Eivind and Nakken, Sigve and Pineda, Marta and Due{\~ n}as, Nuria and Brunet, Joan and Green, Kate and Lalloo, Fiona and Newton, Katie and Crosbie, Emma J. and Mints, Miriam and Tjandra, Douglas and Neffa, Florencia and Esperon, Patricia and Kariv, Revital and Rosner, Guy and Pavicic, Walter Hern{\' a}n and Kalfayan, Pablo and Torrezan, Giovana Tardin and Bassaneze, Thiago and Martin, Claudia and Moslein, Gabriela and Ahadova, Aysel and Kloor, Matthias and Sampson, Julian R. and Jenkins, Mark A.},
journaltitle = {Hereditary Cancer in Clinical Practice},
shortjournal = {Hered Cancer Clin Pract},
doi = {10.1186/s13053-022-00241-1},
issn = {1897-4287},
number = {1},
date = {2022-10-01},
language = {en},
publisher = {{Springer Science and Business Media LLC}},
title = {Colorectal cancer incidences in {Lynch} syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium},
url = {http://dx.doi.org/10.1186/s13053-022-00241-1},
volume = {20},
}
The development and continuous optimization of newborn screening (NBS) programs remains an important and challenging task due to the low prevalence of screened diseases and high sensitivity requirements for screening methods. Recently, different machine learning (ML) methods have been applied to support NBS. However, most studies only focus on single diseases or specific ML techniques making it difficult to draw conclusions on which methods are best to implement. Therefore, we performed a systematic literature review of peer-reviewed publications on ML-based NBS methods. Overall, 125 related papers, published in the past two decades, were collected for the study, and 17 met the inclusion criteria. We analyzed the opportunities and challenges of ML methods for NBS including data preprocessing, classification models and pattern recognition methods based on their underlying approaches, data requirements, interpretability on a modular level, and performance. In general, ML methods have the potential to reduce the false positive rate and identify so far unknown metabolic patterns within NBS data. Our analysis revealed, that, among the presented, logistic regression analysis and support vector machines seem to be valuable candidates for NBS. However, due to the variety of diseases and methods, a general recommendation for a single method in NBS is not possible. Instead, these methods should be further investigated and compared to other approaches in comprehensive studies as they show promising results in NBS applications.
Illustration of machine learning pipeline in NBS
The classification model is the essential part of the ML pipeline in NBS including the interpretable and non-interpretable classification methods and their performance optimization. Data preprocessing is an optional module applied before the classification model. It can include data sampling, feature selection and feature construction methods. Pattern recognition is applied after the classification method evaluating feature importance for biomarker discovery.
@article{Zaunseder2022Opportunities,
author = {Zaunseder, Elaine and Haupt, Saskia and M{\" u}tze, Ulrike and Garbade, Sven F. and K{\" o}lker, Stefan and Heuveline, Vincent},
journal = {JIMD Reports},
year = {2022},
month = {mar 23},
publisher = {Wiley},
title = {Opportunities and challenges in machine learningbased newborn screening---{A} systematic literature review},
}
@article{Zaunseder2022Opportunities,
abstract = {The development and continuous optimization of newborn screening (NBS) programs remains an important and challenging task due to the low prevalence of screened diseases and high sensitivity requirements for screening methods. Recently, different machine learning (ML) methods have been applied to support NBS. However, most studies only focus on single diseases or specific ML techniques making it difficult to draw conclusions on which methods are best to implement. Therefore, we performed a systematic literature review of peer-reviewed publications on ML-based NBS methods. Overall, 125 related papers, published in the past two decades, were collected for the study, and 17 met the inclusion criteria. We analyzed the opportunities and challenges of ML methods for NBS including data preprocessing, classification models and pattern recognition methods based on their underlying approaches, data requirements, interpretability on a modular level, and performance. In general, ML methods have the potential to reduce the false positive rate and identify so far unknown metabolic patterns within NBS data. Our analysis revealed, that, among the presented, logistic regression analysis and support vector machines seem to be valuable candidates for NBS. However, due to the variety of diseases and methods, a general recommendation for a single method in NBS is not possible. Instead, these methods should be further investigated and compared to other approaches in comprehensive studies as they show promising results in NBS applications.},
author = {Zaunseder, Elaine and Haupt, Saskia and M{\" u}tze, Ulrike and Garbade, Sven F. and K{\" o}lker, Stefan and Heuveline, Vincent},
journaltitle = {JIMD Reports},
shortjournal = {JIMD Reports},
doi = {10.1002/jmd2.12285},
issn = {2192-8312},
date = {2022-03-23},
language = {en},
publisher = {Wiley},
title = {Opportunities and challenges in machine learningbased newborn screening---{A} systematic literature review},
url = {http://dx.doi.org/10.1002/jmd2.12285},
}
Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra- crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene.Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.
Overview of the computational model of colonic crypts
Top: The colonic crypt is represented by a cylinder consisting of stem cells (red) at the bottom, transit- amplifying cells (orange) in the middle and fully-differentiated (FD) cells (green) at the top of the crypt. An active stem cell populates the crypt at any point in time. As we model LS, all cells are initialized with a germline variant in exactly one of the MMR genes. The cylinder is transformed into a rectangle with periodic boundary conditions, where the cells are represented by a Voronoi tessellation. Bottom: For each cell type, we model the cell cycle including cell division, possible mutations in one of the MMR genes, in APC and CTNNB1, and multiple death mechanisms.
@article{Haupt2021computational,
author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journal = {Computational and Systems Oncology},
number = {2},
year = {2021},
month = {jun 21},
publisher = {Wiley},
title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
volume = {1},
}
@article{Haupt2021computational,
abstract = {Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra- crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic \textit{CTNNB1} mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene.Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes \textit{APC} and \textit{CTNNB1}, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The \textit{in silico} experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.},
author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journaltitle = {Computational and Systems Oncology},
shortjournal = {Comp Sys Onco},
doi = {10.1002/cso2.1020},
issn = {2689-9655},
number = {2},
date = {2021-06-21},
language = {en},
publisher = {Wiley},
title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
url = {http://dx.doi.org/10.1002/cso2.1020},
volume = {1},
}
Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.
From the Medical Hypothesis Over the Modeling Approach To the Mathematical Structure.
The medical hypothesis of multiple pathways of carcinogenesis is widely known for various types of cancer. (A) We present a model for this phenomenon at the example of Lynch syndrome, the most common inherited CRC syndrome, with specific key driver events in the MMR genes, CTNNB1, APC, KRAS and TP53. (B) This current medical understanding of carcinogenesis is translated into a mathematical model using a specific dynamical system, which can be represented by a graph structure, where each vertex in the graph represents a genotypic state and the edges correspond to the transition probabilities between those states. Starting with all colonic crypts in the state of all genes being wild-type and a single MMR germline variant due to Lynch syndrome, we are interested in the distribution of the crypts among the graph at different ages of the patient in order to obtain estimates for the number of crypts in specific states, e.g., adenomatous or cancerous states. (C) The underlying matrix of the dynamical system makes use of the Kronecker sum and product. It is a sparse upper triangular matrix accounting for the assumption that mutations cannot be reverted. This allows fast numerical solving by using the matrix exponential. Each nonzero entry of the matrix represents a connection between genotypic states in the graph.
@article{Haupt2021Mathematical,
author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journal = {PLOS Computational Biology},
editor = {Chen, Jing},
number = {5},
year = {2021},
month = {may 18},
pages = {e1008970},
publisher = {Public Library of Science (PLoS)},
title = {Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with {Kronecker} structure},
volume = {17},
}
@article{Haupt2021Mathematical,
abstract = {Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in \textit{APC}, \textit{CTNNB1}, \textit{KRAS} and \textit{TP53} are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic \textit{CTNNB1} mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient \textit{APC}-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.},
author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journaltitle = {PLOS Computational Biology},
shortjournal = {PLoS Comput Biol},
doi = {10.1371/journal.pcbi.1008970},
editor = {Chen, Jing},
issn = {1553-7358},
number = {5},
date = {2021-05-18},
language = {en},
pages = {e1008970},
eid = {e1008970},
eprint = {34003820},
eprinttype = {pubmed},
publisher = {Public Library of Science (PLoS)},
title = {Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with {Kronecker} structure},
url = {http://dx.doi.org/10.1371/journal.pcbi.1008970},
volume = {17},
}
Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.
Overview of the computational model of colonic crypts
Top: The colonic crypt is represented by a cylinder consisting of stem cells (red) at the bottom, transit- amplifying cells (orange) in the middle and fully-differentiated (FD) cells (green) at the top of the crypt. An active stem cell populates the crypt at any point in time. As we model LS, all cells are initialized with a germline variant in exactly one of the MMR genes. The cylinder is transformed into a rectangle with periodic boundary conditions, where the cells are represented by a Voronoi tessellation. Bottom: For each cell type, we model the cell cycle including cell division, possible mutations in one of the MMR genes, in APC and CTNNB1, and multiple death mechanisms.
@article{Haupt2020computational,
author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journal = {bioRxiv},
year = {2020},
month = {dec 29},
publisher = {Cold Spring Harbor Laboratory},
title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
}
@article{Haupt2020computational,
abstract = {Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic \textit{CTNNB1} mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes \textit{APC} and \textit{CTNNB1}, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The \textit{in silico} experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.},
author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journaltitle = {bioRxiv},
doi = {10.1101/2020.12.29.424555},
date = {2020-12-29},
publisher = {Cold Spring Harbor Laboratory},
title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
url = {http://dx.doi.org/10.1101/2020.12.29.424555},
}
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.
@article{Ballhausen2020shared,
author = {Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Haupt, Saskia and Pfaffendorf, Elisabeth and Seidler, Florian and Witt, Johannes and Hernandez Sanchez, Alejandro and Urban, Katharina and Draxlbauer, Markus and Krausert, Sonja and Ahadova, Aysel and Kalteis, Martin Simon and Pfuderer, Pauline L. and Heid, Daniel and Stichel, Damian and Gebert, Johannes and Bonsack, Maria and Schott, Sarah and Bl{\" a}ker, Hendrik and Sepp{\" a}l{\" a}, Toni and Mecklin, Jukka-Pekka and Ten Broeke, Sanne and Nielsen, Maartje and Heuveline, Vincent and Krzykalla, Julia and Benner, Axel and Riemer, Angelika Beate and von Knebel Doeberitz, Magnus and Kloor, Matthias},
journal = {Nature Communications},
number = {1},
year = {2020},
month = {sep 21},
publisher = {{Springer Science and Business Media LLC}},
title = {The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution},
volume = {11},
}
@article{Ballhausen2020shared,
abstract = {The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with \textit{Beta-2-microglobulin} mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.},
author = {Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Haupt, Saskia and Pfaffendorf, Elisabeth and Seidler, Florian and Witt, Johannes and Hernandez Sanchez, Alejandro and Urban, Katharina and Draxlbauer, Markus and Krausert, Sonja and Ahadova, Aysel and Kalteis, Martin Simon and Pfuderer, Pauline L. and Heid, Daniel and Stichel, Damian and Gebert, Johannes and Bonsack, Maria and Schott, Sarah and Bl{\" a}ker, Hendrik and Sepp{\" a}l{\" a}, Toni and Mecklin, Jukka-Pekka and Ten Broeke, Sanne and Nielsen, Maartje and Heuveline, Vincent and Krzykalla, Julia and Benner, Axel and Riemer, Angelika Beate and von Knebel Doeberitz, Magnus and Kloor, Matthias},
journaltitle = {Nature Communications},
shortjournal = {Nat Commun},
doi = {10.1038/s41467-020-18514-5},
issn = {2041-1723},
number = {1},
date = {2020-09-21},
language = {en},
eprint = {32958755},
eprinttype = {pubmed},
publisher = {{Springer Science and Business Media LLC}},
title = {The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution},
url = {http://dx.doi.org/10.1038/s41467-020-18514-5},
volume = {11},
}
H. BlĂ€ker, S. Haupt, M. Morak, E. HolinskiâFeder, A. Arnold, D. Horst, J. SieberâFrank, F. Seidler, M. Winterfeld, E. Alwers, J. ChangâClaude, H. Brenner, W. Roth, C. Engel, M. Löffler, G. Möslein, H. Schackert, J. Weitz, C. Perne, S. Aretz, R. HĂŒneburg, W. Schmiegel, D. Vangala, N. Rahner, V. SteinkeâLange, V. Heuveline, M. von Knebel Doeberitz, A. Ahadova, M. Hoffmeister, M. Kloor, The German Consortium for Familial Intestinal Cancer: Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics. International Journal of Cancer, September 2020 DOI: 10.1002/ijc.33273
BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC).Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6 %) harbored BRAF mutations. Six of seven LS patients with BRAF-mutant CRC and reported age were < 50âyears. Among 339 of 756 (44.8 %) of BRAF mutations detected in unselected MSI CRC, only 2 of 339 (0.6 %) BRAF mutations were detected in patients < 50âyears. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age < 50âyears. BRAF testing in patients < 50âyears carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients < 50âyears to genetic counseling without BRAF testing.
â
BRAF mutation testing correctly identifies sporadic MSI CRC patients and saves germline analysis costs in patients aged â„60, whereas in patients aged < 50âyears, BRAF mutation testing leads to misclassification of true LS carriers as sporadic MSI CRC patients and to increased costs of analyses
@article{Blaker2020Age,
author = {Bl{\" a}ker, Hendrik and Haupt, Saskia and Morak, Monika and HolinskiFeder, Elke and Arnold, Alexander and Horst, David and SieberFrank, Julia and Seidler, Florian and Winterfeld, Moritz and Alwers, Elizabeth and ChangClaude, Jenny and Brenner, Hermann and Roth, Wilfried and Engel, Christoph and L{\" o}ffler, Markus and M{\" o}slein, Gabriela and Schackert, HansKonrad and Weitz, J{\" u}rgen and Perne, Claudia and Aretz, Stefan and H{\" u}neburg, Robert and Schmiegel, Wolff and Vangala, Deepak and Rahner, Nils and SteinkeLange, Verena and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Ahadova, Aysel and Hoffmeister, Michael and Kloor, Matthias},
journal = {International Journal of Cancer},
number = {10},
year = {2020},
month = {sep 14},
pages = {2801--2810},
publisher = {Wiley},
title = {Age-dependent performance of \textit{{BRAF}} mutation testing in {Lynch} syndrome diagnostics},
volume = {147},
}
@article{Blaker2020Age,
abstract = {BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC).Current international diagnostic guidelines recommend \textit{BRAF} mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of \textit{BRAF} testing in LS diagnostics. We systematically compared the prevalence of \textit{BRAF} mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of \textit{BRAF} testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6 %) harbored \textit{BRAF} mutations. Six of seven LS patients with \textit{BRAF}-mutant CRC and reported age were \textless{} 50 years. Among 339 of 756 (44.8 %) of \textit{BRAF} mutations detected in unselected MSI CRC, only 2 of 339 (0.6 %) \textit{BRAF} mutations were detected in patients \textless{} 50 years. The inclusion of \textit{BRAF} testing led to high risk of missing LS patients and increased costs at age \textless{} 50 years. \textit{BRAF} testing in patients \textless{} 50 years carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients \textless{} 50 years to genetic counseling without \textit{BRAF} testing.},
author = {Bl{\" a}ker, Hendrik and Haupt, Saskia and Morak, Monika and HolinskiFeder, Elke and Arnold, Alexander and Horst, David and SieberFrank, Julia and Seidler, Florian and Winterfeld, Moritz and Alwers, Elizabeth and ChangClaude, Jenny and Brenner, Hermann and Roth, Wilfried and Engel, Christoph and L{\" o}ffler, Markus and M{\" o}slein, Gabriela and Schackert, HansKonrad and Weitz, J{\" u}rgen and Perne, Claudia and Aretz, Stefan and H{\" u}neburg, Robert and Schmiegel, Wolff and Vangala, Deepak and Rahner, Nils and SteinkeLange, Verena and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Ahadova, Aysel and Hoffmeister, Michael and Kloor, Matthias},
journaltitle = {International Journal of Cancer},
shortjournal = {Int. J. Cancer},
doi = {10.1002/ijc.33273},
issn = {0020-7136},
number = {10},
date = {2020-09-14},
language = {en},
pages = {2801--2810},
eprint = {32875553},
eprinttype = {pubmed},
publisher = {Wiley},
title = {Age-dependent performance of \textit{{BRAF}} mutation testing in {Lynch} syndrome diagnostics},
url = {http://dx.doi.org/10.1002/ijc.33273},
volume = {147},
}
Like many other tumors, colorectal cancers develop through multiple pathways containing different driver mutations. This is also true for colorectal carcinogenesis in Lynch syndrome, the most common inherited colorectal cancer syndrome. However, a comprehensive understanding of Lynch syndrome tumor evolution which allows for tailored clinical treatment and even prevention is still lacking. We suggest a linear autonomous dynamical system modeling the evolution of the different pathways. Starting with the gene mutation graphs of the driver genes, we formulate three key assumptions about how these different mutations might be combined. This approach leads to a dynamical system that is built by the Kronecker sum of the adjacency matrices of the gene mutation graphs. This Kronecker structure makes the dynamical system amenable to a thorough mathematical analysis and medical interpretation, even if the number of incorporated genes or possible mutation states is increased. For the case that some of the mathematical key assumptions are not satisfied, we explain possible extensions to our model. Additionally, improved bio-medical measurements or novel medical insights can be integrated into the model in a straightforward manner, as all parameters in the model have a biological interpretation. Modifications of the model are able to account for other forms of colorectal carcinogenesis, such as Lynch-like and familial adenomatous polyposis cases.
From the Medical Hypothesis Over the Modeling Approach To the Mathematical Structure.
The medical hypothesis of multiple pathways in carcinogenesis is widely known for various types of cancer. Left: We present a model for this phenomenon at the example of Lynch syndrome, the most common inherited colorectal cancer syndrome, with specific key driver events in the MMR genes, CTNNB1, APC, KRAS and TP53. Middle: This current medical understanding of carcinogenesis is translated into a mathematical model using a specific dynamical system, which can be represented by a graph structure, where each vertex in the graph represents a genotypic state and the edges correspond to the transition probabilities between those states. Starting with all colonic crypts in the state of all genes being wild-type and a single MMR germline mutation due to Lynch syndrome, we are interested in the distribution of the crypts among the graph at different ages of the patient in order to obtain estimates for the number of crypts in specific states, e.g. adenomatous or cancerous states. Right: The underlying matrix of the dynamical system makes use of the Kronecker sum and product. It is a sparse upper triangular matrix accounting for the assumption that mutations cannot be reverted. This allows fast numerical solving by using the matrix exponential. Each nonzero entry of the matrix represents a connection between genotypic states in the graph.
@article{Haupt2020Mathematical,
author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journal = {bioRxiv},
year = {2020},
month = {aug 14},
publisher = {Cold Spring Harbor Laboratory},
title = {Mathematical {Modeling} of {Multiple} {Pathways} in {Colorectal} {Carcinogenesis} using {Dynamical} {Systems} with {Kronecker} {Structure}},
}
@article{Haupt2020Mathematical,
abstract = {Like many other tumors, colorectal cancers develop through multiple pathways containing different driver mutations. This is also true for colorectal carcinogenesis in Lynch syndrome, the most common inherited colorectal cancer syndrome. However, a comprehensive understanding of Lynch syndrome tumor evolution which allows for tailored clinical treatment and even prevention is still lacking. We suggest a linear autonomous dynamical system modeling the evolution of the different pathways. Starting with the gene mutation graphs of the driver genes, we formulate three key assumptions about how these different mutations might be combined. This approach leads to a dynamical system that is built by the Kronecker sum of the adjacency matrices of the gene mutation graphs. This Kronecker structure makes the dynamical system amenable to a thorough mathematical analysis and medical interpretation, even if the number of incorporated genes or possible mutation states is increased. For the case that some of the mathematical key assumptions are not satisfied, we explain possible extensions to our model. Additionally, improved bio-medical measurements or novel medical insights can be integrated into the model in a straightforward manner, as all parameters in the model have a biological interpretation. Modifications of the model are able to account for other forms of colorectal carcinogenesis, such as Lynch-like and familial adenomatous polyposis cases.},
author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
journaltitle = {bioRxiv},
doi = {10.1101/2020.08.14.250175},
date = {2020-08-14},
publisher = {Cold Spring Harbor Laboratory},
title = {Mathematical {Modeling} of {Multiple} {Pathways} in {Colorectal} {Carcinogenesis} using {Dynamical} {Systems} with {Kronecker} {Structure}},
url = {http://dx.doi.org/10.1101/2020.08.14.250175},
}
2019
H. BlĂ€ker, S. Haupt, M. Morak, E. Holinski-Feder, A. Arnold, D. Horst, J. Sieber-Frank, F. Seidler, M. von Winterfeld, E. Alwers, J. Chang-Claude, H. Brenner, W. Roth, C. Engel, M. Löffler, G. Möslein, H. Schackert, J. Weitz, C. Perne, S. Aretz, R. HĂŒneburg, W. Schmiegel, D. Vangala, N. Rahner, V. Steinke-Lange, V. Heuveline, M. von Knebel Doeberitz, A. Ahadova, M. Hoffmeister, M. Kloor, the German Consortium for Familial Intestinal Cancer: BRAF mutation testing of MSI CRCs in Lynch syndrome diagnostics: performance and efficiency according to patient's age. medRxiv, October 2019. Preprint DOI: 10.1101/19009274
Background and aimsBRAF V600E mutations have been reported to be associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic BRAF mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic BRAF-mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of BRAF testing in LS diagnostics may be age-dependent. Methods We systematically compared the prevalence of BRAF V600E mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of the BRAF testing for exclusion of LS was performed. Results Among 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harbored BRAF mutations. 6/7 LS patients with BRAF-mutant CRC and reported age were <50 years. Among unselected MSI CRCs, 44.8% (339/756) harbored BRAF mutations, 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50, BRAF mutations were detected only in 0.6% (2/339), and the inclusion of BRAF testing led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups. ConclusionBRAF testing in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without prior BRAF testing.
@article{Blaker2019BRAF,
author = {Bl{\" a}ker, Hendrik and Haupt, Saskia and Morak, Monika and Holinski-Feder, Elke and Arnold, Alexander and Horst, David and Sieber-Frank, Julia and Seidler, Florian and von Winterfeld, Moritz and Alwers, Elizabeth and Chang-Claude, Jenny and Brenner, Hermann and Roth, Wilfried and Engel, Christoph and L{\" o}ffler, Markus and M{\" o}slein, Gabriela and Schackert, Hans-Konrad and Weitz, J{\" u}rgen and Perne, Claudia and Aretz, Stefan and H{\" u}neburg, Robert and Schmiegel, Wolff and Vangala, Deepak and Rahner, Nils and Steinke-Lange, Verena and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Ahadova, Aysel and Hoffmeister, Michael and Kloor, Matthias},
journal = {medRxiv},
year = {2019},
month = {oct 16},
publisher = {Cold Spring Harbor Laboratory},
title = {\textit{{BRAF}} mutation testing of {MSI} {CRCs} in {Lynch} syndrome diagnostics: performance and efficiency according to patient's age},
}
@article{Blaker2019BRAF,
abstract = {\textbf{Background and aims} \textit{BRAF} V600E mutations have been reported to be associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic \textit{BRAF} mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic \textit{BRAF}-mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of \textit{BRAF} testing in LS diagnostics may be age-dependent. \textbf{Methods} We systematically compared the prevalence of \textit{BRAF} V600E mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of the \textit{BRAF} testing for exclusion of LS was performed. \textbf{Results} Among 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harbored \textit{BRAF} mutations. 6/7 LS patients with \textit{BRAF}-mutant CRC and reported age were <50 years. Among unselected MSI CRCs, 44.8% (339/756) harbored \textit{BRAF} mutations, 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50, \textit{BRAF} mutations were detected only in 0.6% (2/339), and the inclusion of \textit{BRAF} testing led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups. \textbf{Conclusion} \textit{BRAF} testing in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without prior \textit{BRAF} testing.},
author = {Bl{\" a}ker, Hendrik and Haupt, Saskia and Morak, Monika and Holinski-Feder, Elke and Arnold, Alexander and Horst, David and Sieber-Frank, Julia and Seidler, Florian and von Winterfeld, Moritz and Alwers, Elizabeth and Chang-Claude, Jenny and Brenner, Hermann and Roth, Wilfried and Engel, Christoph and L{\" o}ffler, Markus and M{\" o}slein, Gabriela and Schackert, Hans-Konrad and Weitz, J{\" u}rgen and Perne, Claudia and Aretz, Stefan and H{\" u}neburg, Robert and Schmiegel, Wolff and Vangala, Deepak and Rahner, Nils and Steinke-Lange, Verena and Heuveline, Vincent and von Knebel Doeberitz, Magnus and Ahadova, Aysel and Hoffmeister, Michael and Kloor, Matthias},
journaltitle = {medRxiv},
doi = {10.1101/19009274},
date = {2019-10-16},
publisher = {Cold Spring Harbor Laboratory},
title = {\textit{{BRAF}} mutation testing of {MSI} {CRCs} in {Lynch} syndrome diagnostics: performance and efficiency according to patient's age},
url = {http://dx.doi.org/10.1101/19009274},
}
A. Ballhausen, M. Przybilla, M. Jendrusch, S. Haupt, E. Pfaffendorf, M. Draxlbauer, F. Seidler, S. Krausert, A. Ahadova, M. Kalteis, D. Heid, J. Gebert, M. Bonsack, S. Schott, H. BlÀker, T. SeppÀlÀ, J. Mecklin, S. Broeke, M. Nielsen, V. Heuveline, J. Krzykalla, A. Benner, A. Riemer, M. von Knebel Doeberitz, M. Kloor: The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution. bioRxiv, July 2019. Preprint DOI: 10.1101/691469
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.
@article{Ballhausen2019shared,
author = {Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Haupt, Saskia and Pfaffendorf, Elisabeth and Draxlbauer, Markus and Seidler, Florian and Krausert, Sonja and Ahadova, Aysel and Kalteis, Martin Simon and Heid, Daniel and Gebert, Johannes and Bonsack, Maria and Schott, Sarah and Bl{\" a}ker, Hendrik and Sepp{\" a}l{\" a}, Toni and Mecklin, Jukka-Pekka and Broeke, Sanne Ten and Nielsen, Maartje and Heuveline, Vincent and Krzykalla, Julia and Benner, Axel and Riemer, Angelika Beate and von Knebel Doeberitz, Magnus and Kloor, Matthias},
journal = {bioRxiv},
year = {2019},
month = {jul 16},
publisher = {Cold Spring Harbor Laboratory},
title = {The shared neoantigen landscape of {MSI} cancers reflects immunoediting during tumor evolution},
}
@article{Ballhausen2019shared,
abstract = {The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced \textit{neo}antigens. Such \textit{neo}antigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to \textit{neo}antigen-inducing translational frameshifts. The abundance of mutational \textit{neo}antigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor \textit{neo}antigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic \textit{neo}antigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting \textit{neo}antigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.},
author = {Ballhausen, Alexej and Przybilla, Moritz Jakob and Jendrusch, Michael and Haupt, Saskia and Pfaffendorf, Elisabeth and Draxlbauer, Markus and Seidler, Florian and Krausert, Sonja and Ahadova, Aysel and Kalteis, Martin Simon and Heid, Daniel and Gebert, Johannes and Bonsack, Maria and Schott, Sarah and Bl{\" a}ker, Hendrik and Sepp{\" a}l{\" a}, Toni and Mecklin, Jukka-Pekka and Broeke, Sanne Ten and Nielsen, Maartje and Heuveline, Vincent and Krzykalla, Julia and Benner, Axel and Riemer, Angelika Beate and von Knebel Doeberitz, Magnus and Kloor, Matthias},
journaltitle = {bioRxiv},
doi = {10.1101/691469},
date = {2019-07-16},
publisher = {Cold Spring Harbor Laboratory},
title = {The shared neoantigen landscape of {MSI} cancers reflects immunoediting during tumor evolution},
url = {http://dx.doi.org/10.1101/691469},
}
2017
S. Gawlok, P. Gerstner, S. Haupt, V. Heuveline, J. Kratzke, P. Lösel, K. Mang, M. Schmidtobreick, N. Schoch, N. Schween, J. Schwegler, C. Song, M. Wlotzka: HiFlow3 â Technical Report on Release 2.0. Preprint Series of the Engineering Mathematics and Computing Lab, November 2017 DOI: 10.11588/EMCLPP.2017.06.42879
HiFlow3 Version 2.0 continues the path as a multi-purpose finite element software, which provides powerful tools for efficient and accurate solution of a wide range of problems modeled by partial differen- tial equations (PDEs). New features and functionalities, which allow to run numerical simulations with more advanced solution algorithms and discretizations in comparison to previous releases of HiFlow3, have been implemented. These comprise Uncertainty Quantification (UQ), energy-efficient multigrid techniques, Schur complement solvers for saddle-point problems, extended third-party library support, and adaptive local mesh refinement in a parallel computing environment. Furthermore, HiFlow3 has been successfully integrated into advanced and state-of-the-art simulation environments by means of the Medical Simulation Markup Language (MSML), for example.
The presented new algorithms and features as well as general under-the-hood improvements have enabled excellent and relevant research activities in the fields of both medical engineering and meteorol- ogy and environmental sciences. The described show cases demonstrate the potential and advantages, which HiFlow3 can offer in performing a numerical simulation by means of finite element methods. Especially, the high performance computing capabilities of HiFlow3 â not only in the mentioned fields of applications, but also in general â have been significantly improved in Version 2.0.
@article{Gawlok2017HiFlow3,
author = {Gawlok, Simon and Gerstner, Philipp and Haupt, Saskia and Heuveline, Vincent and Kratzke, Jonas and L{\" o}sel, Philipp and Mang, Katrin and Schmidtobreick, Mareike and Schoch, Nicolai and Schween, Nils and Schwegler, Jonathan and Song, Chen and Wlotzka, Martin},
journal = {Preprint Series of the Engineering Mathematics and Computing Lab},
year = {2017},
month = {nov 22},
pages = {No 06 (2017): HiFlow3 -- Technical Report on Release 2.0},
publisher = {Heidelberg University, Interdisciplinary Center for Scientific Computing (IWR)},
title = {HiFlow3 -- {Technical} {Report} on {Release} 2.0},
}
@article{Gawlok2017HiFlow3,
abstract = {HiFlow3 Version 2.0 continues the path as a multi-purpose finite element software, which provides powerful tools for efficient and accurate solution of a wide range of problems modeled by partial differen- tial equations (PDEs). New features and functionalities, which allow to run numerical simulations with more advanced solution algorithms and discretizations in comparison to previous releases of HiFlow3, have been implemented. These comprise Uncertainty Quantification (UQ), energy-efficient multigrid techniques, Schur complement solvers for saddle-point problems, extended third-party library support, and adaptive local mesh refinement in a parallel computing environment. Furthermore, HiFlow3 has been successfully integrated into advanced and state-of-the-art simulation environments by means of the Medical Simulation Markup Language (MSML), for example.
The presented new algorithms and features as well as general under-the-hood improvements have enabled excellent and relevant research activities in the fields of both medical engineering and meteorol- ogy and environmental sciences. The described show cases demonstrate the potential and advantages, which HiFlow3 can offer in performing a numerical simulation by means of finite element methods. Especially, the high performance computing capabilities of HiFlow3 -- not only in the mentioned fields of applications, but also in general -- have been significantly improved in Version 2.0.},
author = {Gawlok, Simon and Gerstner, Philipp and Haupt, Saskia and Heuveline, Vincent and Kratzke, Jonas and L{\" o}sel, Philipp and Mang, Katrin and Schmidtobreick, Mareike and Schoch, Nicolai and Schween, Nils and Schwegler, Jonathan and Song, Chen and Wlotzka, Martin},
journaltitle = {Preprint Series of the Engineering Mathematics and Computing Lab},
doi = {10.11588/EMCLPP.2017.06.42879},
date = {2017-11-22},
language = {en},
pages = {No 06 (2017): HiFlow3 -- Technical Report on Release 2.0},
publisher = {Heidelberg University, Interdisciplinary Center for Scientific Computing (IWR)},
title = {HiFlow3 -- {Technical} {Report} on {Release} 2.0},
url = {https://journals.ub.uni-heidelberg.de/index.php/emcl-pp/article/view/42879},
}
