Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer

Abstract

Background The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7). Conclusion 5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer. Impact Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.

Association between 5p12 Genomic Markers and Breast Cancer Susceptibility: Evidence from 19 Case-Control Studies

“…Results from subgroup analyses on ER status of tumors were in agreement with previous reports [5], [25]. Findings from previous studies suggested that several SNPs are predominantly associated with ER-positive BC: 2q35-rs13387042 [22], TNRC9-rs3803662 [25], [37], 8q24-rs13281615 [38], FGFR2-rs2981582 [39]. The present findings support the notion that ER-positive and ER-negative tumors have different genetic components to their risks.…”

“…Stratification of tumors by ER status indicated that the two SNPs (rs4415084 and rs10941679) on 5p12 confer risk, preferentially for ER-positive tumors, with no risk for ER-negative BC. Results from subgroup analyses on ER status of tumors were in agreement with previous reports [5], [25]. Findings from previous studies suggested that several SNPs are predominantly associated with ER-positive BC: 2q35-rs13387042 [22], TNRC9-rs3803662 [25], [37], 8q24-rs13281615 [38], FGFR2-rs2981582 [39].…”

“…Such result could be due to the limited number of studies among Africans/African-Americans, which had insufficient statistical power to detect a slight effect or different linkage disequilibrium (LD) pattern of the two polymorphisms among Africans. Besides, the frequencies of the risk-association alleles in 5p12 are similar in European and Asian populations, but substantially lower in African descent [25], [29]–[31]. Furthermore, ER status may be particularly important given that some GWAS findings are specific to ER-positive and ER-negative cancers [5], [33] and because a higher proportion of African American are diagnosed with ER-negative cancers [34], [35], resulting in risk differences.…”

Reproductive windows, genetic loci, and breast cancer risk

“…Our results also suggest potential interaction between standardize age at first birth and rs10941679 (5p12) (P=0.04) in which the positive association was mainly observed in women with the variant (AG/GG) allele. rs10941679 has been frequently associated with breast cancer risk (7,24,25) and is in linkage disequilibrium with MRPS30 , a gene implicated in apoptosis and estrogen-receptor positive breast cancer (26,27). The biologic mechanisms which could cause an interaction between rs10941679 and standardized age at first birth have not been identified.…”

Estimating single nucleotide polymorphism associations using pedigree data: applications to breast cancer

“…At the time of analysis, 24 SNPs had been shown to be associated with BC risk, primarily through large population-based case–control studies (Supplementary Table 1) (Cox et al , 2007; Easton et al , 2007; Stacey et al , 2007, 2010; Ahmed et al , 2009; Thomas et al , 2009; Antoniou et al , 2010; Turnbull et al , 2010; Fletcher et al , 2011; Milne et al , 2011; Ghoussaini et al , 2012; Hein et al , 2012). We applied the pedigree RL approach to estimate SNP associations with BC risk using data from 736 families recruited on the basis of strong FH of BC and a set of unrelated unaffected controls.…”