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1. Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Author

Philip S. Robinson, Laura E. Thomas, Federico Abascal, Hyunchul Jung, Luke M. R. Harvey, Hannah D. West, Sigurgeir Olafsson, Bernard C. H. Lee, Tim H. H. Coorens, Henry Lee-Six, Laura Butlin, Nicola Lander, Rebekah Truscott, Mathijs A. Sanders, Stefanie V. Lensing, Simon J. A. Buczacki, Rogier ten Hoopen, Nicholas Coleman, Roxanne Brunton-Sim, Simon Rushbrook, Kourosh Saeb-Parsy, Fiona Lalloo, Peter J. Campbell, Iñigo Martincorena, Julian R. Sampson, and Michael R. Stratton

Subjects
Science
Abstract

Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.

Published
2022
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2. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Claire Palles, Hannah D. West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith E. Grolleman, Erik A.M. Jansen, Helen Curley, Laura Chegwidden, Edward H. Arbe-Barnes, Nicola Lander, Rebekah Truscott, Judith Pagan, Ashish Bajel, Kitty Sherwood, Lynn Martin, Huw Thomas, Demetra Georgiou, Florentia Fostira, Yael Goldberg, David J. Adams, Simone A.M. van der Biezen, Michael Christie, Mark Clendenning, Laura E. Thomas, Constantinos Deltas, Aleksandar J. Dimovski, Dagmara Dymerska, Jan Lubinski, Khalid Mahmood, Rachel S. van der Post, Mathijs Sanders, Jürgen Weitz, Jenny C. Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo-Pac, Giulio Caravagna, William Cross, Daniel Chubb, Anna Frangou, Andreas J. Gruber, Ben Kinnersley, Boris Noyvert, David Church, Trevor Graham, Richard Houlston, Nuria Lopez-Bigas, Andrea Sottoriva, David Wedge, Mark A. Jenkins, Roland P. Kuiper, Andrew W. Roberts, Jeremy P. Cheadle, Marjolijn J.L. Ligtenberg, Nicoline Hoogerbrugge, Viktor H. Koelzer, Andres Dacal Rivas, Ingrid M. Winship, Clara Ruiz Ponte, Daniel D. Buchanan, Derek G. Power, Andrew Green, Ian P.M. Tomlinson, Julian R. Sampson, Ian J. Majewski, Richarda M. de Voer, Hematology, Palles, Claire, West, Hannah D, Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E, Jansen, Erik A M, Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H, Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J, van der Biezen, Simone A M, Christie, Michael, Clendenning, Mark, Thomas, Laura E, Deltas, Constantino, Dimovski, Aleksandar J, Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S, Sanders, Mathij, Weitz, Jürgen, Taylor, Jenny C, Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J, Kinnersley, Ben, Noyvert, Bori, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Sottoriva, Andrea, Wedge, David, Jenkins, Mark A, Kuiper, Roland P, Roberts, Andrew W, Cheadle, Jeremy P, Ligtenberg, Marjolijn J L, Hoogerbrugge, Nicoline, Koelzer, Viktor H, Rivas, Andres Dacal, Winship, Ingrid M, Ponte, Clara Ruiz, Buchanan, Daniel D, Power, Derek G, Green, Andrew, Tomlinson, Ian P M, Sampson, Julian R, Majewski, Ian J, and de Voer, Richarda M

Subjects
Uveal Neoplasms, Endodeoxyribonucleases, 5′-methylcytosine deamination, polyposis, colorectal cancer, Colorectal Neoplasm, mutational signature, Germ Cell, Endodeoxyribonuclease, Germ Cells, Adenomatous Polyposis Coli, ddc:570, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], mutator phenotype, Genetics, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Colorectal Neoplasms, polyposi, Genetics (clinical), Human
Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access) We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

3. Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Author

Inigo Martincorena, Hannah West, Philip S. Robinson, Federico Abascal, Hyunchul Jung, Laura Butlin, Nicola Lander, Laura E. Thomas, Roxanne Brunton-Sim, Rogier ten Hoopen, Tim H. H. Coorens, Michael R. Stratton, Henry Lee-Six, Simon M. Rushbrook, Kourosh Saeb-Parsy, Mathijs A. Sanders, Bernard C H Lee, Luke M. R. Harvey, Fiona Lalloo, Nicholas Coleman, Peter J. Campbell, Sigurgeir Olafsson, Simon J.A. Buczacki, Julian R. Sampson, and Stefanie V Lensing

Subjects
Genetics, Mutation rate, Mutation, Germline mutation, MUTYH, Somatic cell, Point mutation, medicine, Base excision repair, Biology, medicine.disease_cause, Germline
Abstract

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequenced normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 5-fold in all individuals, except for one showing a 33-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C>A changes. Different mutation rates and signatures between individuals were likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.Summary

Published
2021

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