Table 1.

Description of the 17 projects included in the study

ProjectRationale for testing SNPs as risk modifiers for breast cancer and ovarian cancer in BRCA-mutation carriersNumber of SNPs includedReference
1Previous data suggested that irradiation response genes whose expression is associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk.18Walker LC et al. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res 2010;12:R102.
2X chromosome SNPs shown to be associated with risk of breast cancer in the CGEMS breast cancer study were considered.11Hunter DJ et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007;39:870–4.
3Previous data suggested that the “del” allele of rs3834129 was associated with increased breast cancer risk in BRCA1-mutation carriers.1Catucci I et al. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers. Breast Cancer Res Treat 2011;125:855–60.
4Search for risk modifiers of BRCA1 5382insC-mutation carriers was performed by a pooled GWAS in 124 women diagnosed with breast cancer (<45 years) and 119 unaffected controls (>50 years at last follow-up) from Poland. The highest-ranked SNPs from the pooled GWAS were selected.137None
5The proposed SNPs are related to genes in regulatory T-cell (Treg) and myeloid-derived suppressor cell (MDSC) pathways. Both pathways play a role in cancer immunosuppression.2,637Schreiber RD et al. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331:1565–70.
6The proposed SNPs were associated with breast density. These SNPs were tested only as modifier of breast cancer risk.72Steude JS et al. Mammographic density and matrix metalloproteinases in breast tissue. Cancer Microenviron 2010;3:57–65. Guo YP et al. Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev 2001;10:243–8. Verheus M et al. Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density. Breast Cancer Res Treat 2008;112:109–22. Diorio C et al. Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol Biomarkers Prev 2008;17:880–8. Diorio C et al. Vitamin D pathway polymorphisms in relation to mammographic breast density. Cancer Epidemiol Biomarkers Prev 2008;17:2505–8.
7SNPs or (SNPs in) genes were considered according to following criteria: (i) affecting circadian rhythms; (ii) interacting with CLOCK; (iii) involved in binding IGF-I to binding proteins; (iv) in progesterone receptor gene and previously found associated with BC and OvC risk; (v) related to disease treatment.20Hoffman AE et al. CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res 2010;70:1459–68. Kelemen LE et al. Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies. Breast Cancer Res 2008;10:R98. Patel AV et al. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One. 2008;3:e2578.
8All these SNPs are located in selenoprotein genes and are involved in selenium metabolism; selenium is known to be associated with cancer risk.11Oestergaard MZ et al. Interactions between genes involved in the antioxidant defence system and breast cancer risk. Br J Cancer 2006;95:525–31. Méplan C et al. Association between Polymorphisms in Glutathione Peroxidase and Selenoprotein P Genes, Glutathione Peroxidase Activity, HRT Use and Breast Cancer Risk PLoS One. 2013;8:e73316. Udler M et al. Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol 2007;25:3015–23. Sutherland A et al. Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer. Genes Nutr 2010;5:215–23.
9Previous data suggested that the rs1045485 SNP modified disease penetrance of breast and ovarian cancer in BRCA1 mutation carriers.1Engel C et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2010;19:2859–68.
10The proposed SNPs are located within the PARP1 gene that plays a key role in the repair of DNA single-strand breaks.3Gonçalves A et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat 2011;127:273–81.
11SNPs were considered because of observations based on evidences of recent positive selection and presence in the same genomic region of genes, (i) coding for BRCA1 interacting proteins; (ii) involved in cancer or breast cancer; (iii) involved in DNA damage response and interacting with TP53.13Voight BF et al. A map of recent positive selection in the human genome. PLoS Biol 2006; 4:e72. Lappalainen T et al. Genomic landscape of positive natural selection in Northern European populations. Eur J Hum Genet 2010;18:471–8.
12Steroid hormones such as estrogens play an important role in the etiology of breast cancer contributing to tumor growth by promoting cell proliferation. SNPs in candidate genes involved in sex steroid metabolism were considered. The SNPs were tested also as breast cancer risk modifiers considering estrogen receptor status of BRCA-mutation carriers (see Supplementary Table S3).139Labrie F et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003;24:152–82.
13RAD51C is a breast cancer gene. SNPs located within, or in close proximity to RAD51C were selected.17Meindl A et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010;42:410–4.
14The highest-ranked SNPs from a GWAS based on 700 hereditary breast cancer cases and 1,200 controls were selected.142None
15SNP rs2981582 in FGFR2 is strongly associated with risk of breast cancer and acting as a risk modifier in BRCA2 mutation carriers. Rs2981582 may also influence the risk of ovarian cancer among BRCA1/2-mutation carriers. This SNP was tested only as modifier of ovarian cancer risk.1Easton DF et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447(7148):1087–93. Hunter DJ et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007;39: 870–4. Antoniou AC et al. Common breast cancer predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 2008;82:937–48.
16The rs10895068 SNP in the promoter of the progesterone receptor (PR) gene (+331G/A) has been reported to be associated with endometrial cancer risk. Our previous study in 220 patients from BC and OC families showed a marginal association of the +331A allele with OC risk. This SNP was tested only as modifier of ovarian cancer risk.1Vivo ID et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 2002;99:12263–68. Romano A et al. Impact of two functional progesterone receptor polymorphisms (PRP): +331G/A and PROGINS on the cancer risks in familial breast/ovarian cancer. Open Cancer J 2007;1:1–8.
17The proposed SNPs were selected according to the hypothesis that different levels of expression of the remaining normal allele in BRCA2 mutation carriers may be associated with variable penetrance of BRCA2 mutations.24Maia AT et al. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. Breast Cancer Res 2012;14:R63.