Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

Claire Palles; Hannah West; Edward Chew; Sara Galavotti; Christoffer Flensburg; Judith Grolleman; Erik Jansen; Helen Curley; Laura Chedwiggen; Edward Arbe-Barnes; Nicola Lander; Rebekah Truscot; Judith Pagan; Ashish Bajel; Kitty Sherwood; Lynn Martin; Huw Thomas; Demetra Georgiou; Florentia Fostira; Yael Goldberg; David Adams; Simone van der Biezen; Michael Christie; Mark Clendenning; Laura Thomas; Constantinos Deltas; Aleksandar Dimovski; Dagmara Dymerska; Jan Lubinski; Khalid Mahmood; Rachel van der Post; Mathijs Sanders; Jurgen Weitz; Jenny Taylor; Clare Turnbull; Lilian Vreede; Tom van Wezel; Celina Whalley; Claudia Arnedo; Giulo Caravagna; William Cross; Daniel Chubb; Anna Frangou; Andreas Gruber; Ben Kinnersley; Boris Noyvert; David Church; Trevor Graham; Richard Houlston; Nuria Lopez; Andrea Sottoriva; David Wedge; Mark Jenkins; Roland Kuiper; Andrew Roberts; Jeremy Cheadle; Marjolijn Ligtenberg; Nicoline Hoogerbrugge; Viktor Koelzer; Andres Dacal Rivas; Ingrid Winship; Clare Ruiz Ponte; Daniel Buchanan; Derek Power; Andrew Green; Ian P.M. Tomlinson; Julian Sampson; Ian Majewski; Richard M. de Voer

doi:10.1016/j.ajhg.2022.03.018

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

Claire Palles, Hannah West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith Grolleman, Erik Jansen, Helen Curley, Laura Chedwiggen, Edward Arbe-Barnes, Nicola Lander, Rebekah Truscot, Judith Pagan, Ashish Bajel, Kitty Sherwood, Lynn Martin, Huw Thomas, Demetra Georgiou, Florentia Fostira, Yael GoldbergDavid Adams, Simone van der Biezen, Michael Christie, Mark Clendenning, Laura Thomas, Constantinos Deltas, Aleksandar Dimovski, Dagmara Dymerska, Jan Lubinski, Khalid Mahmood, Rachel van der Post, Mathijs Sanders, Jurgen Weitz, Jenny Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo, Giulo Caravagna, William Cross, Daniel Chubb, Anna Frangou, Andreas Gruber, Ben Kinnersley, Boris Noyvert, David Church, Trevor Graham, Richard Houlston, Nuria Lopez, Andrea Sottoriva, David Wedge, Mark Jenkins, Roland Kuiper, Andrew Roberts, Jeremy Cheadle, Marjolijn Ligtenberg, Nicoline Hoogerbrugge, Viktor Koelzer, Andres Dacal Rivas, Ingrid Winship, Clare Ruiz Ponte, Daniel Buchanan, Derek Power, Andrew Green, Ian P.M. Tomlinson^*, Julian Sampson, Ian Majewski, Richard M. de Voer

^*Corresponding author for this work

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

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
Journal	American Journal of Human Genetics
Volume	109
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2022.03.018
Publication status	Published - 22 Apr 2022

Keywords

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

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10.1016/j.ajhg.2022.03.018

1-s2.0-S0002929722001148-main
2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Palles, C., West, H., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J., Jansen, E., Curley, H., Chedwiggen, L., Arbe-Barnes, E., Lander, N., Truscot, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H., Georgiou, D., Fostira, F., ... M. de Voer, R. (2022). Germline MBD4-deficiency causes a multi-tumor predisposition syndrome. American Journal of Human Genetics, 109(5), 953-960. https://doi.org/10.1016/j.ajhg.2022.03.018

@article{d1821f4543fb4c8bb76a90842c931c0d,

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 = "Claire Palles and Hannah West and Edward Chew and Sara Galavotti and Christoffer Flensburg and Judith Grolleman and Erik Jansen and Helen Curley and Laura Chedwiggen and Edward Arbe-Barnes and Nicola Lander and Rebekah Truscot 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 David Adams and {van der Biezen}, Simone and Michael Christie and Mark Clendenning and Laura Thomas and Constantinos Deltas and Aleksandar Dimovski and Dagmara Dymerska and Jan Lubinski and Khalid Mahmood and {van der Post}, Rachel and Mathijs Sanders and Jurgen Weitz and Jenny Taylor and Clare Turnbull and Lilian Vreede and {van Wezel}, Tom and Celina Whalley and Claudia Arnedo and Giulo Caravagna and William Cross and Daniel Chubb and Anna Frangou and Andreas Gruber and Ben Kinnersley and Boris Noyvert and David Church and Trevor Graham and Richard Houlston and Nuria Lopez and Andrea Sottoriva and David Wedge and Mark Jenkins and Roland Kuiper and Andrew Roberts and Jeremy Cheadle and Marjolijn Ligtenberg and Nicoline Hoogerbrugge and Viktor Koelzer and {Dacal Rivas}, Andres and Ingrid Winship and {Ruiz Ponte}, Clare and Daniel Buchanan and Derek Power and Andrew Green and Tomlinson, {Ian P.M.} and Julian Sampson and Ian Majewski and {M. de Voer}, Richard",

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 = apr,

day = "22",

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

language = "English",

volume = "109",

pages = "953--960",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

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Palles, C, West, H, Chew, E, Galavotti, S, Flensburg, C, Grolleman, J, Jansen, E, Curley, H, Chedwiggen, L, Arbe-Barnes, E, Lander, N, Truscot, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, D, van der Biezen, S, Christie, M, Clendenning, M, Thomas, L, Deltas, C, Dimovski, A, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, R, Sanders, M, Weitz, J, Taylor, J, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, A, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez, N, Sottoriva, A, Wedge, D, Jenkins, M, Kuiper, R, Roberts, A, Cheadle, J, Ligtenberg, M, Hoogerbrugge, N, Koelzer, V, Dacal Rivas, A, Winship, I, Ruiz Ponte, C, Buchanan, D, Power, D, Green, A, Tomlinson, IPM, Sampson, J, Majewski, I & M. de Voer, R 2022, 'Germline MBD4-deficiency causes a multi-tumor predisposition syndrome', American Journal of Human Genetics, vol. 109, no. 5, pp. 953-960. https://doi.org/10.1016/j.ajhg.2022.03.018

TY - JOUR

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

AU - Palles, Claire

AU - West, Hannah

AU - Chew, Edward

AU - Galavotti, Sara

AU - Flensburg, Christoffer

AU - Grolleman, Judith

AU - Jansen, Erik

AU - Curley, Helen

AU - Chedwiggen, Laura

AU - Arbe-Barnes, Edward

AU - Lander, Nicola

AU - Truscot, 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

AU - van der Biezen, Simone

AU - Christie, Michael

AU - Clendenning, Mark

AU - Thomas, Laura

AU - Deltas, Constantinos

AU - Dimovski, Aleksandar

AU - Dymerska, Dagmara

AU - Lubinski, Jan

AU - Mahmood, Khalid

AU - van der Post, Rachel

AU - Sanders, Mathijs

AU - Weitz, Jurgen

AU - Taylor, Jenny

AU - Turnbull, Clare

AU - Vreede, Lilian

AU - van Wezel, Tom

AU - Whalley, Celina

AU - Arnedo, Claudia

AU - Caravagna, Giulo

AU - Cross, William

AU - Chubb, Daniel

AU - Frangou, Anna

AU - Gruber, Andreas

AU - Kinnersley, Ben

AU - Noyvert, Boris

AU - Church, David

AU - Graham, Trevor

AU - Houlston, Richard

AU - Lopez, Nuria

AU - Sottoriva, Andrea

AU - Wedge, David

AU - Jenkins, Mark

AU - Kuiper, Roland

AU - Roberts, Andrew

AU - Cheadle, Jeremy

AU - Ligtenberg, Marjolijn

AU - Hoogerbrugge, Nicoline

AU - Koelzer, Viktor

AU - Dacal Rivas, Andres

AU - Winship, Ingrid

AU - Ruiz Ponte, Clare

AU - Buchanan, Daniel

AU - Power, Derek

AU - Green, Andrew

AU - Tomlinson, Ian P.M.

AU - Sampson, Julian

AU - Majewski, Ian

AU - M. de Voer, Richard

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 - 2022/4/22

Y1 - 2022/4/22

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

U2 - 10.1016/j.ajhg.2022.03.018

DO - 10.1016/j.ajhg.2022.03.018

M3 - Article

VL - 109

SP - 953

EP - 960

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

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