Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

作者：Claire Palles, Hannah D. West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith E. Grolleman, Erik A. M. Jansen, Helen M. Curley, Laura Chegwidden, Edward H. Arbe-Barnes, Nicola Lander, Rebekah Truscott, Judith Pagan, Ashish R. Bajel, Kitty Sherwood, Lynn M. Martin, Huw J. W. Thomas, Demetra Georgiou, Florentia Fostira, Yael Goldberg, David J. Adams, Simone A.M. van der Biezen, Michael Christie, Mark Clendenning, Laura E. Thomas, Constantinos C. Deltas, Aleksandar J Dimovski, Dagmara Dymerska, Jan Lubiński, Khalid Mahmood, Rachel S. van der Post, Mathijs Arnoud Sanders, Jürgen Weitz, Jenny C. Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo-Pac, Giulio Caravagna, William C. H. Cross, Daniel Chubb, Anna Frangou, Andreas J Gruber, Ben Kinnersley, Boris Noyvert, David N. Church, Trevor A. Graham, Richard S. Houlston, Núria López-Bigas, Andrea Sottoriva, David C. Wedge, Mark A. Jenkins, Roland P. Kuiper, Andrew Warwick Roberts, Jeremy P. Cheadle, Marjolijn J. L. Ligtenberg, Nicoline Hoogerbrugge, Viktor Hendrik Koelzer, Andrés Dacal Rivas, Ingrid Winship, Clara Ruiz Ponte, Daniel D. Buchanan, Derek Gerard Power, Andrew Green, Ian P.M. Tomlinson, Julian R. Sampson, Ian J. Majewski, Richarda M. de Voer · 发表于：The American Journal of Human Genetics · 年份：2022 · DOI：10.1016/j.ajhg.2022.03.018 · 被引用次数：82 · 研究领域：Genetic factors in colorectal cancer、Cancer Genomics and Diagnostics、DNA Repair Mechanisms

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.