Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Genomics England Research Consortium; Colorectal Tumour Gene Identification (CORGI) Consortium; WGS500 Consortium

doi:10.1016/j.ajhg.2022.03.018

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Genomics England Research Consortium, Colorectal Tumour Gene Identification (CORGI) Consortium, WGS500 Consortium

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	953-960
Number of pages	8
Journal	American Journal of Human Genetics
Volume	109
Issue number	5
Early online date	22 Apr 2022
DOIs	https://doi.org/10.1016/j.ajhg.2022.03.018
Publication status	Published - 5 May 2022

Bibliographical note

Funding Information:
This study was funded by the Dutch Cancer Society ( KUN2015-7740 ; 12174/2019-1 ), the Sacha Swarttouw-Hijmans Foundation , Cancer Research UK C6199 , Bowel Cancer West David Darke grant , the EU ERC (EVOCAN), the National Health and Medical Research Council of Australia (project 1145912 , program 1113577 , investigator 1174902 ) and the Cancer Council Victoria ( 1181108 ), with fellowship support from the Victorian Cancer Agency (I.J.M., MCRF15018 ), the Alfred Felton Bequest (I.J.M.) and the Leukaemia Foundation of Australia (Bill Long Charitable Trust PhD Clinical Scholarship to E.C.), and Bowel Cancer UK ( CP 18PG0010 ). H.W. is supported by a Ser Cymru II Precision Medicine Fellowship award. Research was also supported by the Australian Cancer Research Foundation , Victorian State Government Operational Infrastructure Support , and Australian Government NHMRC IRIISS. D.D.B. is supported by an NHMRC R.D. Wright Career Development Fellowship ( GNT1125268 ) and NHMRC Emerging Leadership Fellowship ( GNT1194896 ). M.A.J. is supported by NHMRC Leadership Fellowship. The ACCFR is supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551 ). The research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford . J.C.T. discloses that the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. This work received networking support by the Cooperation in Science and Technology Action CA17118 , supported by the European Cooperation in Science and Technology . Further acknowledgments are described in the supplemental information .

Publisher Copyright:
© 2022 The Author(s)

Keywords

5′-methylcytosine deamination
colorectal cancer
mutational signature
mutator phenotype
polyposis

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Cite this

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title = "Germline MBD4 deficiency causes a multi-tumor predisposition syndrome",

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.",

keywords = "5′-methylcytosine deamination, colorectal cancer, mutational signature, mutator phenotype, polyposis",

author = "{Genomics England Research Consortium} and {Colorectal Tumour Gene Identification (CORGI) Consortium} and {WGS500 Consortium} and Claire Palles and West, {Hannah D.} and Edward Chew and Sara Galavotti and Christoffer Flensburg and Grolleman, {Judith E.} and Jansen, {Erik A.m.} and Helen Curley and Laura Chegwidden and Arbe-barnes, {Edward H.} and Nicola Lander and Rebekah Truscott and Judith Pagan and Ashish Bajel and Kitty Sherwood and Lynn Martin and Huw Thomas and Demetra Georgiou and Florentia Fostira and Yael Goldberg and Adams, {David J.} and {Van Der Biezen}, {Simone A.m.} and Michael Christie and Mark Clendenning and Thomas, {Laura E.} and Constantinos Deltas and Dimovski, {Aleksandar J.} and Dagmara Dymerska and Jan Lubinski and Khalid Mahmood and {Van Der Post}, {Rachel S.} and Mathijs Sanders and J{\"u}rgen Weitz and Taylor, {Jenny C.} and Clare Turnbull and Lilian Vreede and {Van Wezel}, Tom and Celina Whalley and Claudia Arnedo-pac and Giulio Caravagna and William Cross and Daniel Chubb and Anna Frangou and Gruber, {Andreas J.} and Ben Kinnersley and Boris Noyvert and David Church and Trevor Graham and Richard Houlston and Nuria Lopez-bigas",

note = "Funding Information: This study was funded by the Dutch Cancer Society ( KUN2015-7740 ; 12174/2019-1 ), the Sacha Swarttouw-Hijmans Foundation , Cancer Research UK C6199 , Bowel Cancer West David Darke grant , the EU ERC (EVOCAN), the National Health and Medical Research Council of Australia (project 1145912 , program 1113577 , investigator 1174902 ) and the Cancer Council Victoria ( 1181108 ), with fellowship support from the Victorian Cancer Agency (I.J.M., MCRF15018 ), the Alfred Felton Bequest (I.J.M.) and the Leukaemia Foundation of Australia (Bill Long Charitable Trust PhD Clinical Scholarship to E.C.), and Bowel Cancer UK ( CP 18PG0010 ). H.W. is supported by a Ser Cymru II Precision Medicine Fellowship award. Research was also supported by the Australian Cancer Research Foundation , Victorian State Government Operational Infrastructure Support , and Australian Government NHMRC IRIISS. D.D.B. is supported by an NHMRC R.D. Wright Career Development Fellowship ( GNT1125268 ) and NHMRC Emerging Leadership Fellowship ( GNT1194896 ). M.A.J. is supported by NHMRC Leadership Fellowship. The ACCFR is supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551 ). The research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford . J.C.T. discloses that the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. This work received networking support by the Cooperation in Science and Technology Action CA17118 , supported by the European Cooperation in Science and Technology . Further acknowledgments are described in the supplemental information . Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = may,

day = "5",

doi = "10.1016/j.ajhg.2022.03.018",

language = "English",

volume = "109",

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journal = "American Journal of Human Genetics",

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T1 - Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

AU - Genomics England Research Consortium

AU - Colorectal Tumour Gene Identification (CORGI) Consortium

AU - WGS500 Consortium

AU - Palles, Claire

AU - West, Hannah D.

AU - Chew, Edward

AU - Galavotti, Sara

AU - Flensburg, Christoffer

AU - Grolleman, Judith E.

AU - Jansen, Erik A.m.

AU - Curley, Helen

AU - Chegwidden, Laura

AU - Arbe-barnes, Edward H.

AU - Lander, Nicola

AU - Truscott, Rebekah

AU - Pagan, Judith

AU - Bajel, Ashish

AU - Sherwood, Kitty

AU - Martin, Lynn

AU - Thomas, Huw

AU - Georgiou, Demetra

AU - Fostira, Florentia

AU - Goldberg, Yael

AU - Adams, David J.

AU - Van Der Biezen, Simone A.m.

AU - Christie, Michael

AU - Clendenning, Mark

AU - Thomas, Laura E.

AU - Deltas, Constantinos

AU - Dimovski, Aleksandar J.

AU - Dymerska, Dagmara

AU - Lubinski, Jan

AU - Mahmood, Khalid

AU - Van Der Post, Rachel S.

AU - Sanders, Mathijs

AU - Weitz, Jürgen

AU - Taylor, Jenny C.

AU - Turnbull, Clare

AU - Vreede, Lilian

AU - Van Wezel, Tom

AU - Whalley, Celina

AU - Arnedo-pac, Claudia

AU - Caravagna, Giulio

AU - Cross, William

AU - Chubb, Daniel

AU - Frangou, Anna

AU - Gruber, Andreas J.

AU - Kinnersley, Ben

AU - Noyvert, Boris

AU - Church, David

AU - Graham, Trevor

AU - Houlston, Richard

AU - Lopez-bigas, Nuria

N1 - Funding Information: This study was funded by the Dutch Cancer Society ( KUN2015-7740 ; 12174/2019-1 ), the Sacha Swarttouw-Hijmans Foundation , Cancer Research UK C6199 , Bowel Cancer West David Darke grant , the EU ERC (EVOCAN), the National Health and Medical Research Council of Australia (project 1145912 , program 1113577 , investigator 1174902 ) and the Cancer Council Victoria ( 1181108 ), with fellowship support from the Victorian Cancer Agency (I.J.M., MCRF15018 ), the Alfred Felton Bequest (I.J.M.) and the Leukaemia Foundation of Australia (Bill Long Charitable Trust PhD Clinical Scholarship to E.C.), and Bowel Cancer UK ( CP 18PG0010 ). H.W. is supported by a Ser Cymru II Precision Medicine Fellowship award. Research was also supported by the Australian Cancer Research Foundation , Victorian State Government Operational Infrastructure Support , and Australian Government NHMRC IRIISS. D.D.B. is supported by an NHMRC R.D. Wright Career Development Fellowship ( GNT1125268 ) and NHMRC Emerging Leadership Fellowship ( GNT1194896 ). M.A.J. is supported by NHMRC Leadership Fellowship. The ACCFR is supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551 ). The research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford . J.C.T. discloses that the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. This work received networking support by the Cooperation in Science and Technology Action CA17118 , supported by the European Cooperation in Science and Technology . Further acknowledgments are described in the supplemental information . Publisher Copyright: © 2022 The Author(s)

PY - 2022/5/5

Y1 - 2022/5/5

N2 - 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.

AB - 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.

KW - 5′-methylcytosine deamination

KW - colorectal cancer

KW - mutational signature

KW - mutator phenotype

KW - polyposis

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U2 - 10.1016/j.ajhg.2022.03.018

DO - 10.1016/j.ajhg.2022.03.018

M3 - Article

SN - 0002-9297

VL - 109

SP - 953

EP - 960

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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