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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 maintenan...

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Autores principales: Rizzolo, Piera, Silvestri, Valentina, Bucalo, Agostino, Zelli, Veronica, Valentini, Virginia, Catucci, Irene, Zanna, Ines, Masala, Giovanna, Bianchi, Simonetta, Spinelli, Alessandro Mauro, Tommasi, Stefania, Tibiletti, Maria Grazia, Russo, Antonio, Varesco, Liliana, Coppa, Anna, Calistri, Daniele, Cortesi, Laura, Viel, Alessandra, Bonanni, Bernardo, Azzollini, Jacopo, Manoukian, Siranoush, Montagna, Marco, Radice, Paolo, Palli, Domenico, Peterlongo, Paolo, Ottini, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288482/
https://www.ncbi.nlm.nih.gov/pubmed/30564557
http://dx.doi.org/10.3389/fonc.2018.00583
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author Rizzolo, Piera
Silvestri, Valentina
Bucalo, Agostino
Zelli, Veronica
Valentini, Virginia
Catucci, Irene
Zanna, Ines
Masala, Giovanna
Bianchi, Simonetta
Spinelli, Alessandro Mauro
Tommasi, Stefania
Tibiletti, Maria Grazia
Russo, Antonio
Varesco, Liliana
Coppa, Anna
Calistri, Daniele
Cortesi, Laura
Viel, Alessandra
Bonanni, Bernardo
Azzollini, Jacopo
Manoukian, Siranoush
Montagna, Marco
Radice, Paolo
Palli, Domenico
Peterlongo, Paolo
Ottini, Laura
author_facet Rizzolo, Piera
Silvestri, Valentina
Bucalo, Agostino
Zelli, Veronica
Valentini, Virginia
Catucci, Irene
Zanna, Ines
Masala, Giovanna
Bianchi, Simonetta
Spinelli, Alessandro Mauro
Tommasi, Stefania
Tibiletti, Maria Grazia
Russo, Antonio
Varesco, Liliana
Coppa, Anna
Calistri, Daniele
Cortesi, Laura
Viel, Alessandra
Bonanni, Bernardo
Azzollini, Jacopo
Manoukian, Siranoush
Montagna, Marco
Radice, Paolo
Palli, Domenico
Peterlongo, Paolo
Ottini, Laura
author_sort Rizzolo, Piera
collection PubMed
description 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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spelling pubmed-62884822018-12-18 Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy Rizzolo, Piera Silvestri, Valentina Bucalo, Agostino Zelli, Veronica Valentini, Virginia Catucci, Irene Zanna, Ines Masala, Giovanna Bianchi, Simonetta Spinelli, Alessandro Mauro Tommasi, Stefania Tibiletti, Maria Grazia Russo, Antonio Varesco, Liliana Coppa, Anna Calistri, Daniele Cortesi, Laura Viel, Alessandra Bonanni, Bernardo Azzollini, Jacopo Manoukian, Siranoush Montagna, Marco Radice, Paolo Palli, Domenico Peterlongo, Paolo Ottini, Laura Front Oncol Oncology 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. Frontiers Media S.A. 2018-12-04 /pmc/articles/PMC6288482/ /pubmed/30564557 http://dx.doi.org/10.3389/fonc.2018.00583 Text en Copyright © 2018 Rizzolo, Silvestri, Bucalo, Zelli, Valentini, Catucci, Zanna, Masala, Bianchi, Spinelli, Tommasi, Tibiletti, Russo, Varesco, Coppa, Calistri, Cortesi, Viel, Bonanni, Azzollini, Manoukian, Montagna, Radice, Palli, Peterlongo and Ottini. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Rizzolo, Piera
Silvestri, Valentina
Bucalo, Agostino
Zelli, Veronica
Valentini, Virginia
Catucci, Irene
Zanna, Ines
Masala, Giovanna
Bianchi, Simonetta
Spinelli, Alessandro Mauro
Tommasi, Stefania
Tibiletti, Maria Grazia
Russo, Antonio
Varesco, Liliana
Coppa, Anna
Calistri, Daniele
Cortesi, Laura
Viel, Alessandra
Bonanni, Bernardo
Azzollini, Jacopo
Manoukian, Siranoush
Montagna, Marco
Radice, Paolo
Palli, Domenico
Peterlongo, Paolo
Ottini, Laura
Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title_full Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title_fullStr Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title_full_unstemmed Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title_short Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy
title_sort contribution of mutyh variants to male breast cancer risk: results from a multicenter study in italy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288482/
https://www.ncbi.nlm.nih.gov/pubmed/30564557
http://dx.doi.org/10.3389/fonc.2018.00583
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