Male Breast Cancer Susceptibility Research Articles

Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study

BackgroundGermline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients. MethodsWe performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. ResultsPVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88–6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17–45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12–20.56; p = 0.035). ConclusionsThis study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

Penetrance of male breast cancer susceptibility genes: a systematic review.

Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance. A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study. Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant. This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.

Abstract PS8-40: Penetrance of male breast cancer susceptibility genes: A systematic review

Abstract Background: Family history is one of the strongest predisposing factors for male breast cancer (MBC). Several MBC susceptibility genes have been identified, but the risk of MBC for individuals with a pathogenic variant in these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes. Methods: A search query was developed to identify MBC-related abstracts indexed in PubMed, with the followings structure: "Breast Neoplasms, Male"[Mesh] OR (((“Men”[MESH]) OR (male*[TIAB]) OR (man[TIAB]) OR (men[TIAB])) AND ((“Breast Neoplasms”[MESH]) OR (Breast Cancer*[TIAB]) OR (Breast neoplasm*[TIAB]))). A validated natural language processing (NLP) method was applied to retrieve and classify abstracts reporting penetrance estimates. Abstracts labeled as relevant were manually reviewed. The full-text papers of identified penetrance studies were then annotated to extract MBC risk data. These penetrance studies’ bibliographies were also reviewed to ensure comprehensiveness. Results: We identified 17 penetrance studies from 11,799 abstracts, covering five MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2 (Table 1). 53% of these studies were case-control studies, while the rest were cohort studies. Odds ratio (OR), cumulative risk (CR), and relative risk (RR) were three commonly reported risk measures. For BRCA2, eight out of nine studies reported significantly increased risk of MBC or a lifetime CR of over 6%; only one study reported an increased but not statistically significant risk. For BRCA1, one out of six studies reported an elevated lifetime CR of 5.8%, while a second reported a minor increase (OR=1.49) that was statistically significant. The risks reported in the remaining four studies showed no statistically significant increase in risk. Seven studies reported the penetrance of CHEK2, but the risks diverge between the variants tested (Table 2). All three PALB2 studies reported significantly increased risk, while only one ATM study reported an increased risk of MBC, which did not reach statistical significance. Conclusion: To our knowledge, this review provides the first complete set of reported penetrance data for five MBC susceptibility genes. Contradictory MBC risks (significantly increased risk vs. risks that were not statistically significant) were common, which may be due to the studies’ different ascertainment criteria resulting in risk estimates for differing populations. Risk across these studies cannot be directly compared unless studies adjust for ascertainment, though this cataloging of risk defines our current understanding. Table 1: MBC penetrance studiesGeneNumber of StudiesStudy TypeRisk Estimate ReportedMBC RiskBRCA296 Cohort, 3 Case-controlOR, RR, CRStatistically significant increased risk (or lifetime CR &amp;gt; 6%) in 8/9 studiesCHEK277 Case-controlOR, RRVarying risk by variantBRCA163 Cohort, 3 Case-controlOR, RR, CR, HRStatistically significant increased risk in 1/6 studies, one study report lifetime CR = 5.8%PALB231 Cohort, 2 Case-controlOR, RRStatistically significant increased risk in 3/3 studiesATM11 Case-controlORStatistically significant increased risk in 0/1 studyOR: odds ratio; RR: relative risk; CR: cumulative risk; HR: hazard ratio Table 2: As an example: Reported penetrance of CHEK2 for male breast cancer in studies with varying ascertainment criteriaFirst Author, Year of Publication, Patient Population*Pathogenic VariantNumber of CarriersRisk TypeRisk Estimate (95% CI)Statistical SignificanceMeijers-Heijboer H, 2002, Multiple Countries1100delC57RR10.28 (3.54-29.87)YesSyrjakoski K, 2004, Finland1100delC28OR1.27 (0.04-7.92)NoWasielewski M, 2009, Netherlands1100delC21OR4.1 (1.2-14.3)YesPritzlaff M, 2017, USAAll441OR2.4 (1.4-3.9)Yes1100delC135OR3.8 (1.7-7.8)YesI157T238OR1.3 (0.5-3.0)NoHallamies S, 2017, Finland1100delC30OR4.47 (1.51-13.18)YesI157T104OR1.12 (0.4-3.13)NoLu HM, 2019, USANot specifiedNot specifiedOR1.66 (0.04-10.34)NoKleiblova P, 2019, Czech RepublicTruncations3OR20.21 (3.5-80.0)YesDeleterious missense1OR11.87 (0.25-100.83)NoIntermediate missense2OR1.3 (0.15-5.07)NoNeutral missense2OR9.07 (0.98-40.41)NoOR: odds ratio; RR: relative risk* All studies in Table 2 are case-control studies Citation Format: Reem S Chamseddine, Jin Wang, Kanhua Yin, Preeti Singh, Jingan Zhou, Danielle Braun, Mark E Robson, Kevin S Hughes. Penetrance of male breast cancer susceptibility genes: A systematic review [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-40.

Family history of breast cancer in men with non-BRCA male breast cancer: implications for cancer risk counseling.

The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2. We conducted an unmatched case-control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing. Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR 4.7; 95% CI 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR 7.8; 95% CI 5.2, 11.6), for probands and FDR diagnosed at age < 45years (OR 6.9; 95% CI 3.9, 12.4), and for family history of MBC (OR 17.9; 95% CI 7.6, 42.1). Findings were confirmed in a sensitivity analysis of MBC cases who tested negative on a 25-gene pan-cancer panel. MBC patients without mutations in BRCA1/2 have significantly higher odds of a family history of breast cancer, suggesting the existence of unidentified MBC susceptibility alleles.

Common Susceptibility Loci for Male Breast Cancer.

BackgroundThe etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10–06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.ResultsThe genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10–08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10–30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients.

Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.

BRCA and PALB2 mutations in a cohort of male breast cancer with one bilateral case.

Male Breast Cancer (MBC) is a rare disease, about 1% of all breast cancers worldwide and less than 1% of cancers occurring in men. The bilateral male breast cancer (bMBC) is extremely rare. Germline mutations of BRCA1/BRCA2 genes are associated with a significantly increased risk of cancer in MBC; the role of PALB2 remains to be clarified. Our main goal was to provide contribution on characterization of BRCA1/BRCA2 and PALB2 mutations in MBC patients. We observed 28 MBC cases; one of them was a bMBC. Screening for BRCA1, BRCA2 and PALB2 genes was performed on all 28 MBC patients. Mutational analysis was extended to family members of mutated patients. In our study, the MBC incidence was 5.2% and for bMBC was 3.6%. Mutation analysis showed pathogenic mutations in 11/28 (39.3%) patients; 2/28 (7.1%) displayed a mutation in BRCA1, 8/28 (28.6%) in BRCA2 and 1/28 (3.6%) in PALB2. Out of 11 mutated patients, one (9.1%) reported a double mutation in BRCA2. Personal history of other cancers was reported in 2/28 (7.1%) patients affected by bladder cancer. A first/second degree family history of breast/ovarian and other cancers occurred in 23/28 (82.1%) patients. Our findings indicate BRCA2 as the main MBC susceptibility gene and describe an increased risk of bMBC and bladder cancer in mutated patients. The identification of mutations in MBC susceptibility genes supports the usage of oncology prevention programs in affected patients and their relatives carrying the mutation.

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.

Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy.

Inherited mutations in BRCA1, and, mainly, BRCA2 genes are associated with increased risk of male breast cancer (MBC). Mutations in PALB2 and CHEK2 genes may also increase MBC risk. Overall, these genes are functionally linked to DNA repair pathways, highlighting the central role of genome maintenance in MBC genetic predisposition. MUTYH is a DNA repair gene whose biallelic germline variants cause MUTYH-associated polyposis (MAP) syndrome. Monoallelic MUTYH variants have been reported in families with both colorectal and breast cancer and there is some evidence on increased breast cancer risk in women with monoallelic variants. In this study, we aimed to investigate whether MUTYH germline variants may contribute to MBC susceptibility. To this aim, we screened the entire coding region of MUTYH in 503 BRCA1/2 mutation negative MBC cases by multigene panel analysis. Moreover, we genotyped selected variants, including p.Tyr179Cys, p.Gly396Asp, p.Arg245His, p.Gly264Trpfs*7, and p.Gln338His, in a total of 560 MBC cases and 1,540 male controls. Biallelic MUTYH pathogenic variants (p.Tyr179Cys/p.Arg241Trp) were identified in one MBC patient with phenotypic manifestation of adenomatous polyposis. Monoallelic pathogenic variants were identified in 14 (2.5%) MBC patients, in particular, p.Tyr179Cys was detected in seven cases, p.Gly396Asp in five cases, p.Arg245His and p.Gly264Trpfs*7 in one case each. The majority of MBC cases with MUTYH pathogenic variants had family history of cancer including breast, colorectal, and gastric cancers. In the case-control study, an association between the variant p.Tyr179Cys and increased MBC risk emerged by multivariate analysis [odds ratio (OR) = 4.54; 95% confidence interval (CI): 1.17–17.58; p = 0.028]. Overall, our study suggests that MUTYH pathogenic variants may have a role in MBC and, in particular, the p.Tyr179Cys variant may be a low/moderate penetrance risk allele for MBC. Moreover, our results suggest that MBC may be part of the tumor spectrum associated with MAP syndrome, with implication in the clinical management of patients and their relatives. Large-scale collaborative studies are needed to validate these findings.

Abstract 1236: Insight into genetic susceptibility to BRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Abstract Background: Male breast cancer (MBC) is a rare disease, representing less than 1% of all breast cancers (BC). Although rare, MBC remains a substantial cause for morbidity and mortality in men. MBC etiology appears to be largely associated with genetic factors. Inherited mutations in BRCA2, PALB2 and BRCA1 genes, predispose to MBC and account for about 15% of all cases. Thus, a fraction of MBC cases remains to be assigned to specific genetic factors. Here, we aimed at investigating the genetic component of BRCA1/2 mutation negative MBC cases and at identifying germline mutations that could further explain MBC genetic susceptibility. Materials and methods: We performed a genomic screening of a well-characterized series of 502 BRCA1/2 mutation negative Italian MBC cases by a comprehensive multi-gene custom panel of 50 cancer-related genes, using MiniSeq platform (Illumina). We also compared the main clinical-pathologic characteristics of MBCs in mutation carriers and non-carriers using Fisher exact test and t-test, where appropriate. All statistical analyses were performed with the R software (www.r-project.org). Results: Overall 6% of BRCA1/2 mutation negative MBC cases were found to carry a pathogenic variant in the genes analyzed. In particular, PALB2 and ATM were the most frequently altered genes (1.1% and 0.7%, respectively). Mutations in known/proposed BC genes, such as BARD1, BLM, BRIP1, CASP8, CHEK2, FANCM, NBN, NF1, RAD50, RAD51C and RAD51D, as well as in genes considered not closely related to BC predisposition, such as APC, EPCAM and MUTYH, were also identified. Intriguingly, the same NBN mutation was identified in three unrelated MBC cases. Mutation carriers were more likely to have a personal history of cancer in addition to MBC (p=0.0045) and family history of cancer other than breast and ovarian cancer (p=0.0004). Conclusions: This study may help to gain more insight into the genetic susceptibility of MBC. Our results support the central role of PALB2 in MBC susceptibility, point to a relevant role of ATM and confirm a low impact of CHEK2 mutations on MBC predisposition in the Italian population. Considering that pathogenic mutations were found only in a fraction of the genes analyzed, our data indicate that the identification of the more appropriate genes for the genomic screening of MBC cases is essential in order to develop a comprehensive and specific MBC susceptibility panel with implications for clinical management and counselling of patients and their families. Moreover, our results suggest that multigene testing approach may benefit appropriately selected patients, especially those with a personal or family history of cancer other than breast/ovarian cancer. Study supported by AIRC (IG 16933) to L.O. Citation Format: Piera Rizzolo, Veronica Zelli, Valentina Silvestri, Virginia Valentini, Alessandro Spinelli, Maria Grazia Tibiletti, Antonio Russo, Liliana Varesco, Giuseppe Giannini, Daniele Calistri, Laura Cortesi, Alessandra Viel, Marco Montagna, Paolo Peterlongo, Paolo Radice, Domenico Palli, Laura Ottini. Insight into genetic susceptibility to BRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1236.

A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy

IntroductionBreast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10–15% of all cases.FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. MethodsWe screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. ResultsTwo FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). ConclusionRare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.

Family history of breast cancer in non-BRCA male breast cancer: A case-control study.

e13032 Background: Approximately 85% of male breast cancer (MBC) patients test negative for a BRCA mutation, and the role of genetic predisposition is unclear. Cancer risk counseling for unaffected relatives of BRCA-negative MBC patients relies on accurate cancer risk estimates, but there is limited data on the risk of breast cancer (BC) for relatives of these men. We characterized the association between MBC and family history of BC in patients who test negative for BRCA mutations in order to facilitate cancer risk counseling and to explore the possibility of unidentified MBC susceptibility alleles. Methods: We performed a case-control study of patients who had full length sequencing and large-rearrangement analysis for germline mutations in BRCA1/2 or the mismatch repair (MMR) genes at a commercial laboratory from 2006-2012. Cases were MBC patients who tested negative for a BRCA1/2 mutation (n = 3,647); controls were male colon cancer patients who tested negative for mutations in MMR genes (n = 4,269). Information on family history of BC was ascertained from test request forms completed by the ordering healthcare provider at the time of testing. Unconditional multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between family history of BC in first- (FDR) and second-degree relatives (SDR) and MBC with adjustment for potential confounders (age, ethnicity, year of testing). Results: Compared to controls, MBC cases had higher odds of BC in a FDR or SDR (OR = 4.7; 95% CI 4.1, 5.3). Associations were strongest for family history of BC in 1 female FDR (OR = 3.9; 95% CI: 3.3, 4.6), ≥2 female FDR (OR = 7.5; 95% CI 5.0, 11.4), BC in a FDR &lt; 45 years old (for cases diagnosed &lt; 45, OR = 6.9; 95% CI 3.9, 12.4), a male FDR or SDR with BC (OR = 17.9; 95% CI 7.6, 42.1), and both a male and female FDR or SDR with BC (OR = 15.7; 95%CI 4.4, 55.3). Conclusions: MBC patients who test negative for a BRCA mutation have significantly higher odds of reporting family members affected by breast cancer, particularly with affected FDR &lt; 45 years old, multiple affected relatives, and male relatives with BC. This data can guide risk counseling in MBC families, and suggests the existence of unidentified MBC susceptibility alleles.

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

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance 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 age-matched 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 ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized 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.