Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy

Abstract

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common lowpenetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 agematched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/ TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ERtumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ERtumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and wellcharacterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Increased risk of breast cancer in individuals carrying the TNRC9 rs3803662 C>T polymorphism: a meta-analysis of case-control studies

“…In total, 18 studies involving 44,820 cases and 58,316 controls met the inclusion criteria and were used in pooled analyses (Antoniou et al, 2008;Garcia-Closas et al, 2008;Li et al, 2009;Mcinerney et al, 2009;Gorodnova et al, 2010;Latif et al, 2010;Liang et al, 2010;Tamimi et al, 2010;Campa et al, 2011;Han et al, 2011;Slattery et al, 2011;Harlid et al, 2012;Shan et al, 2012;Mizoo et al, 2013;Ottini et al, 2013;Chen et al, 2014;Elematore et al, 2014). The primary features of these investigations are shown in Table 1.…”

Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: Results from a multicenter study in Italy

“…Cases, together with their clinical-pathologic characteristics, were recruited in the frame of the ongoing Italian Multicenter Study on MBC, as previously described [24,27]. Overall, mean age at first BC diagnosis was 61.3 years (SD 11.8); 152 cases (39.4%) reported first-degree family history of breast and/or ovarian cancer and 61 cases (15.8%) had a personal history of other cancers (16 prostate, 9 colorectal and 6 bladder cancers).…”

“…DNA was extracted and quantified as already described [24]. MBC cases and controls were genotyped by using MALDI-TOF spectrophotometric mass determination of allele specific primer extension products with Sequenom's MassARRAY platform and iPLEX technology (Sequenom, San Diego, USA).…”

“…In particular, rs1314913 was found specifically associated with increased BC risk in men, whereas rs3803662 was found associated with increased BC risk also in women [23]. Furthermore, by gene candidate approach ESR1 locus was found to be associated with BC risk in men, and, in particular, with increased risk in oestrogen receptor (ER) negative MBC cases and in male BRCA1/2 mutation carriers [22,24].…”

“…By contrast, only a few studies addressed the role of low-penetrance alleles in MBC susceptibility [22][23][24].…”