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

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Title: Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
Authors: Piera Rizzolo, Valentina Silvestri, Agostino Bucalo, Veronica Zelli, Virginia Valentini, Irene Catucci, Ines Zanna, Giovanna Masala, Simonetta Bianchi, Alessandro Mauro Spinelli, Stefania Tommasi, Maria Grazia Tibiletti, Antonio Russo, Liliana Varesco, Anna Coppa, Daniele Calistri, Laura Cortesi, Alessandra Viel, Bernardo Bonanni, Jacopo Azzollini, Siranoush Manoukian, Marco Montagna, Paolo Radice, Domenico Palli, Paolo Peterlongo, Laura Ottini
Source: Frontiers in Oncology, Vol 8 (2018)
Publisher Information: Frontiers Media S.A., 2018.
Publication Year: 2018
Collection: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Subject Terms: male breast cancer, genetic susceptibility, BRCA1/2, MUTYH, NGS, MUTYH-associated polyposis (MAP) syndrome, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2234-943X
Relation: https://www.frontiersin.org/article/10.3389/fonc.2018.00583/full; https://doaj.org/toc/2234-943X
DOI: 10.3389/fonc.2018.00583
Access URL: https://doaj.org/article/eda859ef5e1044f1885ede042020027d
Accession Number: edsdoj.859ef5e1044f1885ede042020027d
Database: Directory of Open Access Journals
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  Data: 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.
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