Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.
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Authors
Palles, C
West, HD
Chew, E
Galavotti, S
Flensburg, C
Grolleman, JE
Jansen, EAM
Curley, H
Chegwidden, L
Arbe-Barnes, EH
Lander, N
Truscott, R
Pagan, J
Bajel, A
Sherwood, K
Martin, L
Thomas, H
Georgiou, D
Fostira, F
Goldberg, Y
Adams, DJ
van der Biezen, SAM
Christie, M
Clendenning, M
Thomas, LE
Deltas, C
Dimovski, AJ
Dymerska, D
Lubinski, J
Mahmood, K
van der Post, RS
Sanders, M
Weitz, J
Taylor, JC
Turnbull, C
Vreede, L
van Wezel, T
Whalley, C
Arnedo-Pac, C
Caravagna, G
Cross, W
Chubb, D
Frangou, A
Gruber, AJ
Kinnersley, B
Noyvert, B
Church, D
Graham, T
Houlston, R
Lopez-Bigas, N
Sottoriva, A
Wedge, D
Genomics England Research Consortium,
CORGI Consortium,
WGS500 Consortium,
Jenkins, MA
Kuiper, RP
Roberts, AW
Cheadle, JP
Ligtenberg, MJL
Hoogerbrugge, N
Koelzer, VH
Rivas, AD
Winship, IM
Ponte, CR
Buchanan, DD
Power, DG
Green, A
Tomlinson, IPM
Sampson, JR
Majewski, IJ
de Voer, RM
West, HD
Chew, E
Galavotti, S
Flensburg, C
Grolleman, JE
Jansen, EAM
Curley, H
Chegwidden, L
Arbe-Barnes, EH
Lander, N
Truscott, R
Pagan, J
Bajel, A
Sherwood, K
Martin, L
Thomas, H
Georgiou, D
Fostira, F
Goldberg, Y
Adams, DJ
van der Biezen, SAM
Christie, M
Clendenning, M
Thomas, LE
Deltas, C
Dimovski, AJ
Dymerska, D
Lubinski, J
Mahmood, K
van der Post, RS
Sanders, M
Weitz, J
Taylor, JC
Turnbull, C
Vreede, L
van Wezel, T
Whalley, C
Arnedo-Pac, C
Caravagna, G
Cross, W
Chubb, D
Frangou, A
Gruber, AJ
Kinnersley, B
Noyvert, B
Church, D
Graham, T
Houlston, R
Lopez-Bigas, N
Sottoriva, A
Wedge, D
Genomics England Research Consortium,
CORGI Consortium,
WGS500 Consortium,
Jenkins, MA
Kuiper, RP
Roberts, AW
Cheadle, JP
Ligtenberg, MJL
Hoogerbrugge, N
Koelzer, VH
Rivas, AD
Winship, IM
Ponte, CR
Buchanan, DD
Power, DG
Green, A
Tomlinson, IPM
Sampson, JR
Majewski, IJ
de Voer, RM
Document Type
Journal Article
Date
2022-05-05
Date Accepted
2022-03-30
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.
Citation
American Journal of Human Genetics, 2022, 109 (5), pp. 953 - 960
Source Title
American Journal of Human Genetics
Publisher
CELL PRESS
ISSN
0002-9297
eISSN
1537-6605
1537-6605
1537-6605
Collections
Research Team
Cancer Genomics
Evol Genomics & Modelling
Evol Genomics & Modelling