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.
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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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