Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

• DOI: 10.1016/j.ajhg.2022.03.018
• Publication Date: 2022-04-22T14:28:40Z
• Authors: Claire Palles; Hannah D. West; Edward Chew; Sara Galavotti; Christoffer Flens...; Judith E. Grolleman; Erik A.M. Jansen; Helen Curley; Laura Chegwidden; Edward H. Arbe-Ba...; 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 d...; Michael Christie; Mark Clendenning; Laura E. Thomas; Constantinos Deltas; Aleksandar J. Dim...; Dagmara Dymerska; Jan Lubinski; Khalid Mahmood; Rachel S. van der...; 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. Li...; Nicoline Hoogerbr...; 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
• Keywords: Uveal Neoplasms; 610; polyposis; colorectal cancer; Colorectal Neoplasm; Germ Cell; 03 medical and health sciences; Endodeoxyribonuclease; Report; mutator phenotype; Humans; Genetic Predisposition to Disease; 5′-methylcytosine deamination; colorectal cancer; mutational signature; mutator phenotype; polyposis; Endodeoxyribonucleases; Genetic Predisposition to Disease; Germ Cells; Germ-Line Mutation; Humans; Adenomatous Polyposis Coli; Colorectal Neoplasms; Uveal Neoplasms; polyposi; Germ-Line Mutation; 0303 health sciences; Endodeoxyribonucleases; 5′-methylcytosine deamination; mutational signature; 3. Good health; Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences; Germ Cells; Adenomatous Polyposis Coli; Colorectal Neoplasms; Human

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.