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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00583/full |
| _version_ | 1811260267316641792 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Piera Rizzolo |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T18:43:55Z |
| format | Article |
| id | doaj.art-eda859ef5e1044f1885ede042020027d |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T18:43:55Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-eda859ef5e1044f1885ede042020027d2022-12-22T03:20:40ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-12-01810.3389/fonc.2018.00583415613Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in ItalyPiera Rizzolo0Valentina Silvestri1Agostino Bucalo2Veronica Zelli3Virginia Valentini4Irene Catucci5Ines Zanna6Giovanna Masala7Simonetta Bianchi8Alessandro Mauro Spinelli9Stefania Tommasi10Maria Grazia Tibiletti11Antonio Russo12Liliana Varesco13Anna Coppa14Daniele Calistri15Laura Cortesi16Alessandra Viel17Bernardo Bonanni18Jacopo Azzollini19Siranoush Manoukian20Marco Montagna21Paolo Radice22Domenico Palli23Paolo Peterlongo24Laura Ottini25Department of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyGenome Diagnostics Program, IFOM - The FIRC Institute of Molecular Oncology, Milan, ItalyCancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, ItalyCancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, ItalyDivision of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, ItalyInstitute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, ItalyMolecular Genetics Laboratory, Istituto Tumori Giovanni Paolo II, Bari, ItalyDipartimento di Patologia, ASST Settelaghi and Centro di Ricerca per lo studio dei tumori eredo-familiari, Università dell'Insubria, Varese, ItalySection of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, ItalyIRCCS Ospedale Policlinico San Martino, Genoa, Italy0Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy1Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy2Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy3Unità di Oncogenetica e Oncogenomica Funzionale, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy4Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO), IRCCS, Milan, Italy5Unità di Genetica Medica, Dipartimento di Oncologia Medica ed Ematologia, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy5Unità di Genetica Medica, Dipartimento di Oncologia Medica ed Ematologia, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy6Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy7Unità di Ricerca Medicina Predittiva: Basi molecolari Rischio genetico e Test genetici, Dipartimento di Ricerca, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, ItalyCancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, ItalyGenome Diagnostics Program, IFOM - The FIRC Institute of Molecular Oncology, Milan, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyInherited 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.https://www.frontiersin.org/article/10.3389/fonc.2018.00583/fullmale breast cancergenetic susceptibilityBRCA1/2MUTYHNGSMUTYH-associated polyposis (MAP) syndrome |
| spellingShingle | 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 Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy Frontiers in Oncology male breast cancer genetic susceptibility BRCA1/2 MUTYH NGS MUTYH-associated polyposis (MAP) syndrome |
| 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 | male breast cancer genetic susceptibility BRCA1/2 MUTYH NGS MUTYH-associated polyposis (MAP) syndrome |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00583/full |
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