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

Bucalo, Agostino; Conti, Giulia; Valentini, Virginia; Capalbo, Carlo; Bruselles, Alessandro; Tartaglia, Marco; Bonanni, Bernardo; Calistri, Daniele; Coppa, Anna; Cortesi, Laura; Giannini, Giuseppe; Gismondi, Viviana; Manoukian, Siranoush; Manzella, Livia; Montagna, Marco; Peterlongo, Paolo; Radice, Paolo; Russo, Antonio; Tibiletti, Maria Grazia; Turchetti, Daniela; Viel, Alessandra; Zanna, Ines; Palli, Domenico; Silvestri, Valentina; Ottini, Laura

doi:10.1016/j.ejca.2023.04.022

Cited by 6 publications

(15 citation statements)

References 42 publications

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“…Previous works have tended to identify genes involved in MBC risk based on either more or less restricted panels of genes on large MBC populations or exome analysis of small MBC populations. Bucalo et al recently screened 1349 MBC cases with a 50-gene panel and reported the involvement of ATM and PALB2 genes in the risk of MBC [ 16 ]. Another study examining 94 genes in 102 Greek MBC patients identified PVs in 6 genes: BRCA2, ATM, BRCA1, CHEK2, PMS2 and FANCL [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, the only clearly identified risk factor for MBC is the presence of a germline pathogenic or likely pathogenic variant (PV or LPV, respectively) in the BRCA2 or BRCA1 genes. Several studies have investigated the involvement of other genes in the risk of developing MBC, with populations ranging from 6 to 767 patients and panels ranging from 16 to 94 genes, predominantly restricted to genes previously implicated in FBC [ 13 , 14 , 15 , 16 ] or even at the exome scale (4600 genes), albeit only including 6 patients [ 17 ]. These studies have demonstrated the presence of PVs associated with the risk of MBC in the PALB2 (OR = 6.6–17.3), CHEK2 (OR = 3.7), ATM and RAD51D (OR = 8.6–10.2) genes (see review [ 18 ]).…”

Section: Introductionmentioning

confidence: 99%

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Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Al Saati,

Vande Perre,

Plenecassagnes

et al. 2023

IJMS

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Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2, other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Al Saati,

Vande Perre,

Plenecassagnes

et al. 2023

IJMS

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“…At the population level, PALB2 PVs showed an increased risk of about fourfold, whereas among familial FBC cases at about eightfold [23]. For male PALB2 PV carriers, a sevenfold increased risk of BC and a cumulative BC risk of 1% to age 80 years were estimated [32,47]. In addition to BC, PALB2 PVs were associated with two-to threefold increased risks of OC in women and pancreatic cancer in both sexes [47].…”

Section: Palb2mentioning

confidence: 95%

“…These genes were generally classified as moderate-penetrance genes since their PVs confer a smaller risk of BC than BRCA1/2 PVs. On the other hand, a small but increasing number of studies applied multigene panel testing to investigate additional genes associated with MBC predisposition [25][26][27][28][29][30][31][32]. Collaborative studies are starting to provide reliable gender-specific cancer risk estimates for BC susceptibility genes [32][33][34].…”

Section: The Genetic Architecture Of Bc Predispositionmentioning

confidence: 99%

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Valentini,

Bucalo,

Conti

et al. 2024

Cancers

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Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.

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“…This was an observational, retrospective study, based on a series of 144 invasive MBC cases collected from five Italian Research Centers participating in the Italian multicenter study on MBC [18]. All patients enrolled had been previously tested for germline pathogenic variants (PVs) in 50 breast cancer predisposition genes, including BRCA1 and BRCA2 [18,19].…”

Section: Methodsmentioning

confidence: 99%

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

Silvestri,

Valentini,

Bucalo

et al. 2024

Cancers

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In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody–drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.

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

Cited by 6 publications

References 42 publications

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

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