Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

被引：28

作者：

Palles, Claire ^{[1
]}

West, Hannah D. ^{[2
]}

Chew, Edward ^{[3
]}

Galavotti, Sara ^{[1
]}

Flensburg, Christoffer ^{[3
]}

Grolleman, Judith E. ^{[4
]}

Jansen, Erik A. M. ^{[4
]}

Curley, Helen ^{[1
]}

Chegwidden, Laura ^{[1
]}

Arbe-Barnes, Edward H. ^{[5
]}

Lander, Nicola ^{[2
]}

Truscott, Rebekah ^{[2
]}

Pagan, Judith ^{[6
]}

Bajel, Ashish ^{[7
,8
]}

Sherwood, Kitty ^{[9
]}

Martin, Lynn ^{[1
]}

Thomas, Huw ^{[10
]}

Georgiou, Demetra ^{[11
,12
]}

Fostira, Florentia ^{[13
]}

Goldberg, Yael ^{[14
,15
]}

Adams, David J. ^{[16
]}

van der Biezen, Simone A. M. ^{[4
]}

Christie, Michael ^{[3
,17
]}

Clendenning, Mark ^{[17
,18
]}

Thomas, Laura E. ^{[19
]}

Deltas, Constantinos ^{[20
,21
]}

Dimovski, Aleksandar J. ^{[22
]}

Dymerska, Dagmara ^{[23
]}

Lubinski, Jan ^{[23
]}

Mahmood, Khalid ^{[17
,18
]}

van der Post, Rachel S. ^{[24
]}

Sanders, Mathijs ^{[25
]}

Weitz, Jurgen ^{[26
]}

Taylor, Jenny C. ^{[27
]}

Turnbull, Clare ^{[28
]}

Vreede, Lilian ^{[4
]}

van Wezel, Tom ^{[29
]}

Whalley, Celina ^{[1
]}

Arnedo-Pac, Claudia ^{[30
]}

Caravagna, Giulio ^{[28
]}

Cross, William ^{[31
]}

Chubb, Daniel ^{[28
]}

Frangou, Anna ^{[5
]}

Gruber, Andreas J. ^{[32
]}

Kinnersley, Ben ^{[28
]}

Noyvert, Boris ^{[1
]}

Church, David ^{[5
]}

Graham, Trevor ^{[33
]}

Houlston, Richard ^{[28
]}

Lopez-Bigas, Nuria ^{[30
]}

机构：

[1] Univ Birmingham, Coll Med & Dent Sci, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands, England

[2] Cardiff Univ, Sch Med, Inst Med Genet, Div Canc & Genet, Cardiff, Wales

[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[4] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Human Genet, Med Ctr, NL-6525 Nijmegen, Netherlands

[5] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[6] Western Gen Hosp, South East Scotland Genet Serv, Mol Genet Lab, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland

[7] Peter MacCallum Canc Ctr, Parkville, Vic, Australia

[8] Royal Melbourne Hosp, Victorian Comprehens Canc Ctr, Parkville, Vic, Australia

[9] Univ Edinburgh, Edinburgh Canc Res Ctr, Crewe Rd, Edinburgh EH4 2XR, Midlothian, Scotland

[10] Imperial Coll London, St Marks Hosp, London, England

[11] Imperial Coll Healthcare Trust, Genom Med, Northwick Pk, Harrow, Middx, England

[12] North West Thames Reg Genet Serv, Northwick Pk, Harrow, Middx, England

[13] NCSR Demokritos, Mol Diagnost Lab, Athens, Greece

[14] Rabin Med Ctr, Raphael Recanati Genet Inst, Beilinson Hosp, Petah Tiqwa, Israel

[15] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[16] Wellcome Genome Campus, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[17] Univ Melbourne, Melbourne Med Sch, Dept Clin Pathol, Colorectal Oncogen Grp, Parkville, Vic, Australia

[18] Univ Melbourne, Victorian Comprehens Canc Ctr, Ctr Canc Res, Parkville, Vic, Australia

[19] Swansea Univ, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales

[20] Univ Cyprus, Ctr Excellence Biobanking, Med Sch, Nicosia, Cyprus

[21] Univ Cyprus, Biomed Res & Mol Med Res Ctr, Med Sch, Nicosia, Cyprus

[22] UKIM Fac Pharm, Ctr Biomol Pharmaceut Anal, Skopje 1000, North Macedonia

[23] Pomeranian Med Univ, Hereditary Canc Ctr, Dept Genet & Pathol, PL-70111 Szczecin, Poland

[24] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pathol, Med Ctr, NL-6525 Nijmegen, Netherlands

[25] Erasmus MC, Dept Hematol, Rotterdam, Netherlands

[26] Tech Univ Dresden, Univ Klinikum Carl Gustav Carus, Dept Surg Res, D-01307 Dresden, Germany

[27] Univ Oxford, Oxford NIHR Biomed Res Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[28] Inst Canc Res, Cotswold Rd, Sutton SM2 5NG, Surrey, England

[29] Leiden Univ, Dept Pathol, Med Ctr, NL-2300 Leiden, Netherlands

[30] Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain

[31] UCL, Canc Inst, 72 Huntley St, London WC1E 6BT, England

[32] Univ Manchester, Manchester Interdisciplinary Bioctr, Manchester M1 7DN, Lancs, England

[33] Queen Mary Univ London, Barts & London Sch Med & Dent, Barts Canc Inst, London, England

[34] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Parkville, Vic, Australia

[35] Princess Maxima Ctr Pediat Oncol, NL-3584 Utrecht, Netherlands

[36] Univ Melbourne, Dept Med Biol, 1G Royal Parade, Parkville, Vic 3052, Australia

[37] Univ Zurich, Univ Hosp Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland

[38] Hosp Lucus Augusti, Inst Invest Sanitaria Santiago, Serv Digest, Lugo, Galicia, Spain

[39] Royal Melbourne Hosp, Genom Med & Family Canc Clin, Melbourne, Vic, Australia

[40] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne Med Sch, Dept Med, Melbourne, Vic, Australia

[41] Fdn Publ Galega Med Xenom SERGAS, Ctr Invest Biomed Red Enfermedades Raras, Inst Invest Sanitaria Santiago, Grp Med Xenom USC, Santiago De Compostela, Galicia, Spain

[42] Cork Univ Hosp, Dept Med Oncol, Cork, Ireland

[43] Childrens Hlth Ireland, Dept Clin Genet, Dublin, Ireland

[44] Univ Coll, Sch Med, Dublin, Ireland

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2022年 / 109卷 / 05期

基金：

澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

MUTATIONS;

D O I：

10.1016/j.ajhg.2022.03.018

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 50 -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.

引用

页码：953 / 960

页数：8

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