Supplementary Figure S1A-G. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Genes up to 500 kb on either side of each new index SNP are shown. All variants nominally associated (P < 0.05) with every cancer type contributing to the corresponding cross-cancer meta-analysis are plotted regardless of the direction of effect across cancers. Supplementary Figure S1A 1
Supplementary Figure S1B 2
Supplementary Figure S1C 3
Supplementary Figure S1D* * The index variant at the new 9q31 breast and ovarian cancer risk locus rs200182588 (gray dot), was a deletion/insertion polymorphism for which no linkage disequilibrium data were available in LocusZoom for the regional association plot. Therefore, the next most significantly associated SNP rs10820601, was used for this plot. 4
Supplementary Figure S1E 5
Supplementary Figure S1F 6
Supplementary Figure S1G 7
Supplementary Figure S2A-B. Box plots showing eqtl associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S2A L3MBTL3 and rs9375701 Alleles (Ref/Alt): C/T Supplementary Figure S2B RCCD1 and rs8037137 Alleles (Ref/Alt): T/C 8
Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta Death Pathway genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend. Supplementary Methods Published Breast, Ovarian, and Prostate Cancer Index SNPs We compiled a list of the most significantly associated SNP, referred to as the index SNP, in every region known to be associated with ovarian, breast and/or prostate cancer risk at genome-wide significance (P < 5 x 10-8 ) in populations of European ancestry. The SNPs were obtained from the publications that reported the largest and most recent genome-wide association meta-analysis for susceptibility to each cancer (1 3). The list included 18 SNPs associated with all invasive and/or serous invasive epithelial ovarian cancer, 92 SNPs associated with overall, ER-positive and/or ER-negative breast cancer, and 100 SNPs associated with prostate cancer (Supplementary Table S1). The ovarian cancer risk SNP rs4691139 was associated with ovarian cancer risk only in BRCA1 mutation carriers (4). Of the 100 prostate cancer risk SNPs, rs636291, was associated specifically with early-onset prostate cancer risk and seven SNPs had been identified at genome-wide significance only after a multi-ancestry meta-analysis that included data from populations of European ancestry (3). These seven SNPs were associated with prostate cancer at P < 6.8 x 10-4 in European ancestry populations (3). For SNPs discovered before the latest publication in each cancer, index SNPs obtained from the most recent publication were identical to those reported in the original publications. The only exception was at the 2q33 breast cancer susceptibility locus where the original SNP (5), rs1045485, was not replicated even at a P < 10-4 threshold in the latest combined analysis (1). This SNP was replaced with rs1830298 (r 2 = 0.05 with rs1045485 in 1000 Genomes 9
European populations, distance between the two SNPs = 32 kb), which did reach genome-wide significance in the same analysis. Overall, the list contained 207 unique index SNPs after accounting for two cross-cancer SNPs (rs10069690 and rs8170) that were both associated with ER-negative breast and serous ovarian cancer risk and one SNP (rs4245739) sharing an association with breast and prostate cancer risk. Sixty of the 207 SNPs were located in 21 1-Mb regions containing index SNPs associated with more than one of the three cancers (Supplementary Table S2). References 1. Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet. 2015;47:373 80. 2. Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet. 2015;47:164 71. 3. Olama AA Al, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet. 2014;46:1103 9. 4. Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 2013;9:e1003212. 5. Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MWR, Pooley KA, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007;39:352 8. 10