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Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Palles, Claire; West, Hannah D; Chew, Edward; Galavotti, Sara; Flensburg, Christoffer; Grolleman, Judith E; Jansen, Erik AM; ... de Voer, Richarda M; + view all (2022) Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. American Journal of Human Genetics , 109 (5) pp. 953-960. 10.1016/j.ajhg.2022.03.018. Green open access

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Abstract

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.

Type: Article
Title: Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajhg.2022.03.018
Publisher version: https://doi.org/10.1016/j.ajhg.2022.03.018
Language: English
Additional information: © 2022 The Author(s). Published under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
Keywords: 5′-methylcytosine deamination, colorectal cancer, mutational signature, mutator phenotype, polyposis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10147919
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