Similarity Measures for Clustering SNP Data

The issue of suitable similarity measures for a particular kind of genetic data – so called SNP data – arises from the GENICA (Interdisciplinary Study Group on Gene Environment Interaction and Breast Cancer in Germany) case-control study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. A single nucleotide polymorphism is a point mutation that is present in at least 1 % of a population. SNPs are the most common form of human genetic variations. In particular, we consider 65 SNP loci and 2 insertions of longer sequences in genes involved in the metabolism of hormones, xenobiotics and drugs as well as in the repair of DNA and signal transduction. Assuming that these single nucleotide changes may lead, for instance, to altered enzymes or to a reduced or enhanced amount of the original enzymes – with each alteration alone having minor effects – we aim to detect combinations of SNPs that under certain environmental conditions increase the risk of sporadic breast cancer. The search for patterns in the present data set may be performed by a variety of clustering and classification approaches. We consider here the problem of suitable measures of proximity of two variables or subjects as an indispensable basis for a further cluster analysis. Generally, clustering approaches are a useful tool to detect structures and to generate hypothesis about potential relationships in complex data situations. Searching for patterns in the data there are two possible objectives: the identification of groups of similar objects or subjects or the identification of groups of similar variables within the whole or within subpopulations. Comparing the individual genetic profiles as well as comparing the genetic information across subpopulations we discuss possible choices of similarity measures, in particular similarity measures based on the counts of matches and mismatches. New matching coefficients are introduced with a more flexible weighting scheme to account for the general problem of the comparison of SNP data: The large proportion of homozygous reference sequences relative to the homo- and heterozygous SNPs is masking the accordances and differences of interest

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.This work was supported by the NHMRC Project Grant (ID#1031333). This work was also supported by Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692)This is the published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00439-014-1515-4

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following estrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95%CI 0.73-0.82, P=2.1x10(-19)) and identify 13 additional linked variants (r(2)>0.8) in the 20Kb linkage block containing the enCNV (P=3.2x10(-15) - 5.6x10(-17)). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5

Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

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Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk

Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.Conceived and designed the experiments: P Hall, FJ Couch, J Simard, D Altshuler, DF Easton, G Chenevix-Trench, AC Antoniou, K Offit. Performed the experiments: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, T Kirchhoff. Analyzed the data: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, L McGuffog, D Barrowdale, AM Dunning, J Simard, D Altshuler, DF Easton, AC Antoniou, K Offit. Contributed reagents/ materials/analysis tools: L McGuffog, D Barrowdale, AM Dunning, A Lee, J Dennis, S Healey, E Dicks, P Soucy, OM Sinilnikova, VS Pankratz, X Wang, RC Eldridge, DC Tessier, D Vincent, F Bacot, FBL Hogervorst, S Peock, D Stoppa-Lyonnet, P Peterlongo, RK Schmutzler, KL Nathanson, M Piedmonte, CF Singer, M Thomassen, TvO Hansen, SL Neuhausen, I Blanco, MH Greene, J Garber, JN Weitzel, IL Andrulis, DE Goldgar, E D’Andrea, T Caldes, H Nevanlinna, A Osorio, EJ van Rensburg, A Arason, G Rennert, AMW van den Ouweland, AH van der Hout, CM Kets, CM Aalfs, JT Wijnen, MGEM Ausems, D Frost, S Ellis, E Fineberg, R Platte, DG Evans, C Jacobs, J Adlard, M Tischkowitz, ME Porteous, F Damiola, L Golmard, L Barjhoux, M Longy, M Belotti, SF Ferrer, S Mazoyer, AB Spurdle, S Manoukian, M Barile, M Genuardi, N Arnold, A Meindl, C Sutter, B Wappenschmidt, SM Domchek, G Pfeiler, E Friedman, UB Jensen, M Robson, S Shah, C Lazaro, PL Mai, J Benitez, MC Southey, MK Schmidt, PA Fasching, J Peto, MK Humphreys, Q Wang, K Michailidou, EJ Sawyer, B Burwinkel, P Gue´nel, SE Bojesen, RL Milne, H Brenner, M Lochmann, K Aittoma¨ ki, T Do¨rk, S Margolin, A Mannermaa, D Lambrechts, J Chang-Claude, P Radice, GG Giles, CA Haiman, R Winqvist, P Devillee, M Garcı´a-Closas, N Schoof, MJ Hooning, A Cox, PDP Pharoah, A Jakubowska, N Orr, A Gonza´lez-Neira, G Pita, MR Alonso, P Hall, FJ Couch, DF Easton, G Chenevix-Trench, AC Antoniou, K Offit. Wrote the paper: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, AC Antoniou, K Offit.Figure S1 Cluster plots for SNPs (A.) rs9348512, (B.) rs619373, and (C.) rs184577.Figure S2 Multidimensional scaling plots of the top two principal components of genomic ancestry of all eligible BRCA2 iCOGS samples plotted with the HapMap CEU, ASI, and YRI samples: (A.) samples from Finland and BRCA2 6174delT carriers highlighted, and (B.) samples, indicated in red, with .19% non- European ancestry were excluded.Figure S3 Quantile–quantile plot comparing expected and observed distributions of P-values. Results displayed (A) for the complete sample, (B) after excluding samples from the GWAS discovery stage, and (C) for the complete sample and a set of SNPs from the iCOGS array that were selected independent from the results of the BRCA2 mutation carriers.Figure S4 Manhattan plot of P-values by chromosomal position for 18,086 SNPs selected on the basis of a previously published genome-wide association study of BRCA2 mutation carriers. Breast cancer associations results based on 4,330 breast cancer cases and 3,881 unaffected BRCA2 carriers.Figure S5 Forest plot of the country-specific, per-allele hazard ratios (HR) and 95% confidence intervals for the association between breast cancer and rs9348512 genotypes.Figure S6 Forest plot of the country-specific, per-allele hazard ratios (HR) and 95% confidence intervals for the association with breast cancer for (A.) rs619373 and (B.) rs184577 genotypes.Table S1 Quality control filtering steps for BRCA2 mutation carriers and SNPs on the COGs array.Table S2 Description of breast cancer affected and unaffected BRCA2 carriers included in the final analysis of the COGs array SNPs.Table S3 Breast cancer hazards ratios (HR) and 95% confidence intervals (CI) for all SNPs with P,1023 in a 500 Mb region around rs9348512 on 6p24 among BRCA2 mutation carriers.Table S4 Associations with SNPs at 6p24, FGF13 and 2p22 and breast and ovarian cancer risk using a competing risk analysis model.Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9x10 8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.This work was supported by the following institutions: iCOGS: The creation of the custom Illumina multiplex chip and the genotyping of the BRCA2 carriers in CIMBA was made possible by grants from the Starr Cancer Consortium I4-A402 (PI: K Offit), the Sandra Taub Memorial Fund of the Breast Cancer Research Foundation (PI: K Offit), the Norman and Carol Stone Cancer Genetics Fund (PI: K Offit), and the European Commission’s Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). AC Antoniou is a Cancer Research UK Senior Cancer Research Fellow. G Chenevix-Trench is an NHMRC Senior Principal Research Fellow. Consortium of Modifiers of BRCA1/2 Associations: The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. S Healey is supported by an NHMRC Program Grant to G Chenevix-Trench. AC Antoniou is a Cancer Research UK Senior Cancer Research Fellow. G Chenevix-Trench is an NHMRC Senior Principal Research Fellow. Amsterdam Breast Cancer Study: The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. Bavarian Breast Cancer Cases and Controls: The work of the BBCC was partly funded by ELAN–Fond of the University Hospital of Erlangen. British Breast Cancer Study: The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). Breast Cancer Family Registry Studies: The Australian Breast Cancer Family Study (ABCFS), New York City (New York Breast CFR), Northern California Breast Cancer Family Registry (NC-BCFR), Ontario Familial Breast Cancer Registry (OFBCR), and Utah (Utah Breast CFR) work was supported by the United States National Cancer Institute, National Institutes of Health (NIH), under RFA-CA-06-503 (P30 CA13696 and P30 ES009089), and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Cancer Prevention Institute of California (U01 CA69417), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. The New York BCFR site was also supported by NIH grants P30 CA13696 and P30 ES009089. MC Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Baltic Familial Breast Ovarian Cancer Consortium: BFBOCC is partly supported by: Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo ve˙zˇio asociacija). 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. Breast Cancer in Galway Genetic Study: Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. BRCA-gene mutations and breast cancer in South African women: BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to EJ van Rensburg NIH R01CA74415 and P30 CA033752. Beckman Research Institute of the City of Hope: SL Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Breast Cancer Study of the University Clinic Heidelberg: The BSUCH study was supported by the Dietmar- Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). Rigshospitalet: The CBCS study was supported by the NEYE Foundation. CECILE Breast Cancer Study: The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Se´curite´ Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). Copenhagen General Population Study: The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. Spanish National Cancer Centre: The CNIO work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilen˜ a Foundation (FMMA) and SAF2010-20493. Spanish National Cancer Centre Breast Cancer Study: The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tema´tica de Investigacio´n Cooperativa en Ca´ncer and grants from the Asociacio´n Espan˜ ola Contra el Ca´ncer and the Fondo de Investigacio´n Sanitario (PI11/00923 and PI081120). City of Hope Cancer Center: The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: JN Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella: CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project ‘‘Hereditary tumors’’), Italian Association for Cancer Research (AIRC, IG 8713), Italian Ministry of Health (Extraordinary National Cancer Program 2006, ‘‘Alleanza contro il Cancro’’ and ‘‘Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association 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 (INT-Institutional strategic projects ‘‘561000’’). German Cancer Research Center: The DKFZ study was supported by the DKFZ. Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland: The DNA HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004- 3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO. Epidemiological study of BRCA1 & BRCA2 mutation carriers: EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. DG Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester. ESTHER Breast Cancer Study: The ESTHER study was supported by a grant from the Baden Wu¨ rttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). German Consortium of Hereditary Breast and Ovarian Cancer: GC-HBOC is supported by the German Cancer Aid (grant no 109076), by the Center for Molecular Medicine Cologne (CMMC), and by Deutsche Krebshilfe (107 352). GC-HBOC is supported by Deutsche Krebshilfe. Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers: The GEMO 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. Gene Environment Interaction and Breast Cancer in Germany: The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Cecilia Zvocec,Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. University of California Los Angeles (UCLA): We thank Joyce Seldon MSGC and Lorna Kwan MPH for assembling the data for this study. University of California San Francisco (UCSF): We would like to thank Ms. Salina Chan for her data management and the following genetic counselors for participant recruitment: Beth Crawford, Nicola Stewart, Julie Mak, and Kate Lamvik. United Kingdom Breakthrough Generations Study (UKBGS): We thank Breakthrough Breast Cancer and the Institute of Cancer Research for support of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses, and other health care providers and health information sources who have contributed to the study. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): We thank Simon Gayther, Susan Ramus, Carole Pye, Patricia Harrington, and Eva Wozniak for their contributions towards the UKFOCR. Victorian Familial Cancer Trials Group (VFCTG): We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification. Krankenhaus, Bonn, Germany. Gynecologic Oncology Group: 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). MH Greene and PL Mai are supported by funding from the Intramural Research Program, NCI. Hospital Clinico San Carlos: HCSC was supported by a grant RD06/0020/0021 from RTICC (ISCIII), Spanish Ministry of Economy and Competitivity. Helsinki Breast Cancer Study: The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473),the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Hannover-Minsk Breast Cancer Study: The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia: HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary: Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/ NA/2008-3/O¨ P-9. Institut Catala` d’Oncologia: The ICO study was supported by the Asociacio´n Espan˜ ola Contra el Ca´ncer, Spanish Health Research Foundation, Ramo´n Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. Iceland Landspitali–University Hospital: The ILUH group was supported by the Icelandic Association ‘‘Walking for Breast Cancer Research’’ and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility: INHERIT 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. J Simard is Chairholder of the Canada Research Chair in Oncogenetics. Istituto Oncologico Veneto: The IOVHBOCS study was supported by Ministero dell’Istruzione, dell’Universita` e della Ricerca and Ministero della Salute (‘‘Progetto Tumori Femminili’’ and RFPS 2006-5-341353, ACC2/R6.9’’). Karolinska Breast Cancer Study: The KARBAC study was supported by the Swedish Cancer Society, the Gustav V Jubilee Foundation, and the Bert von Kantzow Foundation. Kuopio Breast Cancer Project: The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. Kathleen Cuningham Consortium for Research into Familial Breast Cancer: kConFab is supported by grants from the National Breast Cancer Foundation and 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. G Chenevix-Trench and AB Spurdle are NHMRC Senior Research Fellows. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia, and the NHMRC [199600]. G Chenevix-Trench is supported by the NHMRC. The Clinical Follow Up Study (funded 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) Korean Hereditary Breast Cancer Study: KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). Leuven Multidisciplinary Breast Centre: LMBC is supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). D Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. Mammary Carcinoma Risk Factor Investigation: The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Mayo Clinic: 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 Foundation and the Komen Foundation for the Cure. Milan Breast Cancer Study Group: MBCSG was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project ‘‘Hereditary tumors’’), Italian Association for Cancer Research (AIRC, IG 8713), Italian Ministry of Health (‘‘Progetto Tumori Femminili’’), and by Italian citizens who allocated the 561000 share of their tax payment in supp

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following estrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95%CI 0.73-0.82, P=2.1x10(-19)) and identify 13 additional linked variants (r(2)>0.8) in the 20Kb linkage block containing the enCNV (P=3.2x10(-15) - 5.6x10(-17)). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5

MicroRNA Related Polymorphisms and Breast Cancer Risk

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