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Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

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

The American Journal of Human Genetics, Volume: 109, Issue: 5, Pages: 953 - 960

Swansea University Author: Laura Thomas Orcid Logo

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DOI (Published version): 10.1016/j.ajhg.2022.03.018

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...

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Published in: The American Journal of Human Genetics
ISSN: 0002-9297
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa60439
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MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5&#x2032;-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.</abstract><type>Journal Article</type><journal>The American Journal of Human Genetics</journal><volume>109</volume><journalNumber>5</journalNumber><paginationStart>953</paginationStart><paginationEnd>960</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0002-9297</issnPrint><issnElectronic/><keywords>polyposis; colorectal cancer; 5&#x2032;-methylcytosine deamination; mutational signature; mutator phenotype</keywords><publishedDay>5</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-05-05</publishedDate><doi>10.1016/j.ajhg.2022.03.018</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>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.</funders><projectreference/><lastEdited>2022-11-02T11:20:57.1235787</lastEdited><Created>2022-07-11T09:57:53.8435260</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Claire</firstname><surname>Palles</surname><order>1</order></author><author><firstname>Hannah D.</firstname><surname>West</surname><order>2</order></author><author><firstname>Edward</firstname><surname>Chew</surname><order>3</order></author><author><firstname>Sara</firstname><surname>Galavotti</surname><order>4</order></author><author><firstname>Christoffer</firstname><surname>Flensburg</surname><order>5</order></author><author><firstname>Judith E.</firstname><surname>Grolleman</surname><order>6</order></author><author><firstname>Erik A.M.</firstname><surname>Jansen</surname><order>7</order></author><author><firstname>Helen</firstname><surname>Curley</surname><order>8</order></author><author><firstname>Laura</firstname><surname>Chegwidden</surname><order>9</order></author><author><firstname>Edward H.</firstname><surname>Arbe-Barnes</surname><order>10</order></author><author><firstname>Nicola</firstname><surname>Lander</surname><order>11</order></author><author><firstname>Rebekah</firstname><surname>Truscott</surname><order>12</order></author><author><firstname>Judith</firstname><surname>Pagan</surname><order>13</order></author><author><firstname>Ashish</firstname><surname>Bajel</surname><order>14</order></author><author><firstname>Kitty</firstname><surname>Sherwood</surname><order>15</order></author><author><firstname>Lynn</firstname><surname>Martin</surname><order>16</order></author><author><firstname>Huw</firstname><surname>Thomas</surname><order>17</order></author><author><firstname>Demetra</firstname><surname>Georgiou</surname><order>18</order></author><author><firstname>Florentia</firstname><surname>Fostira</surname><order>19</order></author><author><firstname>Yael</firstname><surname>Goldberg</surname><order>20</order></author><author><firstname>David J.</firstname><surname>Adams</surname><order>21</order></author><author><firstname>Simone A.M. van der</firstname><surname>Biezen</surname><order>22</order></author><author><firstname>Michael</firstname><surname>Christie</surname><order>23</order></author><author><firstname>Mark</firstname><surname>Clendenning</surname><order>24</order></author><author><firstname>Laura</firstname><surname>Thomas</surname><orcid>0000-0002-8621-5285</orcid><order>25</order></author><author><firstname>Constantinos</firstname><surname>Deltas</surname><order>26</order></author><author><firstname>Aleksandar J.</firstname><surname>Dimovski</surname><order>27</order></author><author><firstname>Dagmara</firstname><surname>Dymerska</surname><order>28</order></author><author><firstname>Jan</firstname><surname>Lubinski</surname><order>29</order></author><author><firstname>Khalid</firstname><surname>Mahmood</surname><order>30</order></author><author><firstname>Rachel S. van der</firstname><surname>Post</surname><order>31</order></author><author><firstname>Mathijs</firstname><surname>Sanders</surname><order>32</order></author><author><firstname>J&#xFC;rgen</firstname><surname>Weitz</surname><order>33</order></author><author><firstname>Jenny C.</firstname><surname>Taylor</surname><order>34</order></author><author><firstname>Clare</firstname><surname>Turnbull</surname><order>35</order></author><author><firstname>Lilian</firstname><surname>Vreede</surname><order>36</order></author><author><firstname>Tom van</firstname><surname>Wezel</surname><order>37</order></author><author><firstname>Celina</firstname><surname>Whalley</surname><order>38</order></author><author><firstname>Claudia</firstname><surname>Arnedo-Pac</surname><order>39</order></author><author><firstname>Giulio</firstname><surname>Caravagna</surname><order>40</order></author><author><firstname>William</firstname><surname>Cross</surname><order>41</order></author><author><firstname>Daniel</firstname><surname>Chubb</surname><order>42</order></author><author><firstname>Anna</firstname><surname>Frangou</surname><order>43</order></author><author><firstname>Andreas J.</firstname><surname>Gruber</surname><order>44</order></author><author><firstname>Ben</firstname><surname>Kinnersley</surname><order>45</order></author><author><firstname>Boris</firstname><surname>Noyvert</surname><order>46</order></author><author><firstname>David</firstname><surname>Church</surname><order>47</order></author><author><firstname>Trevor</firstname><surname>Graham</surname><order>48</order></author><author><firstname>Richard</firstname><surname>Houlston</surname><order>49</order></author><author><firstname>Nuria</firstname><surname>Lopez-Bigas</surname><order>50</order></author><author><firstname>Andrea</firstname><surname>Sottoriva</surname><order>51</order></author><author><firstname>David</firstname><surname>Wedge</surname><order>52</order></author><author><firstname>Mark A.</firstname><surname>Jenkins</surname><order>53</order></author><author><firstname>Roland P.</firstname><surname>Kuiper</surname><order>54</order></author><author><firstname>Andrew W.</firstname><surname>Roberts</surname><order>55</order></author><author><firstname>Jeremy P.</firstname><surname>Cheadle</surname><order>56</order></author><author><firstname>Marjolijn J.L.</firstname><surname>Ligtenberg</surname><order>57</order></author><author><firstname>Nicoline</firstname><surname>Hoogerbrugge</surname><order>58</order></author><author><firstname>Viktor H.</firstname><surname>Koelzer</surname><order>59</order></author><author><firstname>Andres Dacal</firstname><surname>Rivas</surname><order>60</order></author><author><firstname>Ingrid M.</firstname><surname>Winship</surname><order>61</order></author><author><firstname>Clara Ruiz</firstname><surname>Ponte</surname><order>62</order></author><author><firstname>Daniel D.</firstname><surname>Buchanan</surname><order>63</order></author><author><firstname>Derek 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spelling 2022-11-02T11:20:57.1235787 v2 60439 2022-07-11 Germline MBD4 deficiency causes a multi-tumor predisposition syndrome 6f80a1638d852bd88d37afe3aeb2fb62 0000-0002-8621-5285 Laura Thomas Laura Thomas true false 2022-07-11 BMS 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. Journal Article The American Journal of Human Genetics 109 5 953 960 Elsevier BV 0002-9297 polyposis; colorectal cancer; 5′-methylcytosine deamination; mutational signature; mutator phenotype 5 5 2022 2022-05-05 10.1016/j.ajhg.2022.03.018 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 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. 2022-11-02T11:20:57.1235787 2022-07-11T09:57:53.8435260 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Claire Palles 1 Hannah D. West 2 Edward Chew 3 Sara Galavotti 4 Christoffer Flensburg 5 Judith E. Grolleman 6 Erik A.M. Jansen 7 Helen Curley 8 Laura Chegwidden 9 Edward H. Arbe-Barnes 10 Nicola Lander 11 Rebekah Truscott 12 Judith Pagan 13 Ashish Bajel 14 Kitty Sherwood 15 Lynn Martin 16 Huw Thomas 17 Demetra Georgiou 18 Florentia Fostira 19 Yael Goldberg 20 David J. Adams 21 Simone A.M. van der Biezen 22 Michael Christie 23 Mark Clendenning 24 Laura Thomas 0000-0002-8621-5285 25 Constantinos Deltas 26 Aleksandar J. Dimovski 27 Dagmara Dymerska 28 Jan Lubinski 29 Khalid Mahmood 30 Rachel S. van der Post 31 Mathijs Sanders 32 Jürgen Weitz 33 Jenny C. Taylor 34 Clare Turnbull 35 Lilian Vreede 36 Tom van Wezel 37 Celina Whalley 38 Claudia Arnedo-Pac 39 Giulio Caravagna 40 William Cross 41 Daniel Chubb 42 Anna Frangou 43 Andreas J. Gruber 44 Ben Kinnersley 45 Boris Noyvert 46 David Church 47 Trevor Graham 48 Richard Houlston 49 Nuria Lopez-Bigas 50 Andrea Sottoriva 51 David Wedge 52 Mark A. Jenkins 53 Roland P. Kuiper 54 Andrew W. Roberts 55 Jeremy P. Cheadle 56 Marjolijn J.L. Ligtenberg 57 Nicoline Hoogerbrugge 58 Viktor H. Koelzer 59 Andres Dacal Rivas 60 Ingrid M. Winship 61 Clara Ruiz Ponte 62 Daniel D. Buchanan 63 Derek G. Power 64 Andrew Green 65 Ian P.M. Tomlinson 0000-0003-3037-1470 66 Julian R. Sampson 67 Ian J. Majewski 68 Richarda M. de Voer 0000-0002-8222-0343 69 60439__24550__52cceb5181264cb48fde4d7924e7cc65.pdf 60439.pdf 2022-07-12T13:37:58.2415009 Output 1058923 application/pdf Version of Record true Copyright 2022 The Author(s). This is an open access article under the CC BY license true eng http://creativecommons.org/licenses/by/4.0/
title Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
spellingShingle Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
Laura Thomas
title_short Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
title_full Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
title_fullStr Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
title_full_unstemmed Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
title_sort Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
author_id_str_mv 6f80a1638d852bd88d37afe3aeb2fb62
author_id_fullname_str_mv 6f80a1638d852bd88d37afe3aeb2fb62_***_Laura Thomas
author Laura Thomas
author2 Claire Palles
Hannah D. West
Edward Chew
Sara Galavotti
Christoffer Flensburg
Judith E. Grolleman
Erik A.M. Jansen
Helen Curley
Laura Chegwidden
Edward H. Arbe-Barnes
Nicola Lander
Rebekah Truscott
Judith Pagan
Ashish Bajel
Kitty Sherwood
Lynn Martin
Huw Thomas
Demetra Georgiou
Florentia Fostira
Yael Goldberg
David J. Adams
Simone A.M. van der Biezen
Michael Christie
Mark Clendenning
Laura Thomas
Constantinos Deltas
Aleksandar J. Dimovski
Dagmara Dymerska
Jan Lubinski
Khalid Mahmood
Rachel S. van der Post
Mathijs Sanders
Jürgen Weitz
Jenny C. Taylor
Clare Turnbull
Lilian Vreede
Tom van Wezel
Celina Whalley
Claudia Arnedo-Pac
Giulio Caravagna
William Cross
Daniel Chubb
Anna Frangou
Andreas J. Gruber
Ben Kinnersley
Boris Noyvert
David Church
Trevor Graham
Richard Houlston
Nuria Lopez-Bigas
Andrea Sottoriva
David Wedge
Mark A. Jenkins
Roland P. Kuiper
Andrew W. Roberts
Jeremy P. Cheadle
Marjolijn J.L. Ligtenberg
Nicoline Hoogerbrugge
Viktor H. Koelzer
Andres Dacal Rivas
Ingrid M. Winship
Clara Ruiz Ponte
Daniel D. Buchanan
Derek G. Power
Andrew Green
Ian P.M. Tomlinson
Julian R. Sampson
Ian J. Majewski
Richarda M. de Voer
format Journal article
container_title The American Journal of Human Genetics
container_volume 109
container_issue 5
container_start_page 953
publishDate 2022
institution Swansea University
issn 0002-9297
doi_str_mv 10.1016/j.ajhg.2022.03.018
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2022-05-05T04:18:33Z
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score 11.013619

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