University of Groningen DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers Osorio,

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p,0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03– 1.16), p = 2.7610) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8610). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/ 2 mutation carriers and should be more comprehensively studied. Citation: Osorio A, Milne RL, Kuchenbaecker K, Vaclová T, Pita G, et al. (2014) DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. PLoS Genet 10(4): e1004256. doi:10.1371/journal.pgen.1004256 Editor: Marshall S. Horwitz, University of Washington, United States of America Received October 23, 2013; Accepted February 4, 2014; Published April 3, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: The CNIO study was supported by Mutua Madrileña Foundation (FMMA), Spanish Association against Cancer (AECC08), RTICC 06/0020/1060 and FISPI12/00070. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement nu 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537 the GAME-ON initiative), the Department of Defence (W81XWH10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. SWE-BRCA collaborators are supported by the Swedish Cancer Society. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to EJvR. UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor. UPENN study is supported by Basser Research Center (SMD, KN, TRR), Breast Cancer Research Foundation (KN), Komen Foundation for the Cure (SMD). The Women’s Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). BCFR study: This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC is supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant LIG-07/2012 and Hereditary Cancer Association (Paveldimo vėžio asociacija); Base Excision Repair Genes Are BRCA1/2 Modifiers PLOS Genetics | www.plosgenetics.org 3 April 2014 | Volume 10 | Issue 4 | e1004256 Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 and Liepaja’s municipal council. BRICOH study: NIH R01CA74415 and P30 CA033752. SLN was partially supported by the Morris and Horowitz Families Professorship. CBCS work was supported by the NEYE Foundation. The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: JNW) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The members of CONSIT TEAM were funded by grants from the Italian Association for Cancer Research (AIRC) to PP, LO and PR; FiorGen Foundation for Pharmacogenomics to LP; Associazione CAOS Varese to MGT and by funds from Italian citizens who allocated the 561000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INTInstitutional strategic projects ‘561000’) to SMan and PR. Demokritos: This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program ‘‘Education and Lifelong Learning’’ of the National Strategic Reference Framework (NSRF) Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. Investing in knowledge society through the European Social Fund. We wish to thank Hellenic Cooperative Oncology Group (HeCOG) and the Hellenic Foundation for Cancer Research (HFCR). EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. GE and FLa are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. RE and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. FCCC study: The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GCHBOC) is supported by the German Cancer Aid (grant no 109076, RKS) and by the Center for Molecular Medicine Cologne (CMMC). This study was kindly supported by the German Cancer Aid to RKS (grant no 109076) and by the Center for Molecular Medicine Cologne (CMMC). GEMO study: The study was supported by the Ligue National Contre le Cancer; the Association ‘‘Le cancer du sein, parlons-en!’’ Award; and the Canadian Institutes of Health Research for the ‘‘CIHR Team in Familial Risks of Breast Cancer’’ program. GOG study: This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517), and GOG’s Cancer Prevention and Control Committee (CA 101165). MHG, PLM and Sharon A. Savage were supported by funding from the Intramural Research Program, NCI. This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) CA 27469, CA 37517, and CA 101165. HCSC study was supported by a grant RD06/0020/0021 from RTICC (ISCIII), Spanish Ministry of Economy and Competitivity. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI20073756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745. IHCC study: KJB is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. The ILUH group was supported by the Nordic Cancer Union, Icelandic Association ‘‘Walking for Breast Cancer Research’’ and by the Landspitali University Hospital Research Fund. INHERIT: This work was supported by the Canadian Institutes of Health Research for the ‘‘CIHR Team in Familial Risks of Breast Cancer’’ program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS study was supported by Ministero dell’Istruzione, dell’Università e della Ricerca and Ministero della Salute. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. GCT and Amanda B. Spurdle are NHMRC Senior Research Fellows. MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundatio