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

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 & 6 others Siranoush Manoukian, Marco Montagna, Paolo Radice, Domenico Palli, Paolo Peterlongo, Laura Ottini

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
JournalFrontiers in Oncology
Volume8
DOIs
Publication statusPublished - 2018

Fingerprint

Male Breast Neoplasms
Italy
Multicenter Studies
Breast Neoplasms
DNA Repair
Mutation
Colorectal Neoplasms
BRCA2 Gene
Genes
Penetrance
Genetic Predisposition to Disease

Keywords

  • BRCA1/2
  • breast cancer risk
  • genetic susceptibility
  • male breast cancer
  • MUTYH
  • MUTYH-associated polyposis (MAP) syndrome
  • NGS

Cite this

Rizzolo, P., Silvestri, V., Bucalo, A., Zelli, V., Valentini, V., Catucci, I., ... Ottini, L. (2018). Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy. Frontiers in Oncology, 8. https://doi.org/10.3389/fonc.2018.00583

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.

In: Frontiers in Oncology, Vol. 8, 2018.

Research output: Contribution to journalArticle

Rizzolo, P, Silvestri, V, Bucalo, A, Zelli, V, Valentini, V, Catucci, I, Zanna, I, Masala, G, Bianchi, S, Spinelli, AM, Tommasi, S, Tibiletti, MG, Russo, A, Varesco, L, Coppa, A, Calistri, D, Cortesi, L, Viel, A, Bonanni, B, Azzollini, J, Manoukian, S, Montagna, M, Radice, P, Palli, D, Peterlongo, P & Ottini, L 2018, 'Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy', Frontiers in Oncology, vol. 8. https://doi.org/10.3389/fonc.2018.00583
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. In: Frontiers in Oncology. 2018 ; Vol. 8.
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abstract = "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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T1 - Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy

AU - Rizzolo, Piera

AU - Silvestri, Valentina

AU - Bucalo, Agostino

AU - Zelli, Veronica

AU - Valentini, Virginia

AU - Catucci, Irene

AU - Zanna, Ines

AU - Masala, Giovanna

AU - Bianchi, Simonetta

AU - Spinelli, Alessandro Mauro

AU - Tommasi, Stefania

AU - Tibiletti, Maria Grazia

AU - Russo, Antonio

AU - Varesco, Liliana

AU - Coppa, Anna

AU - Calistri, Daniele

AU - Cortesi, Laura

AU - Viel, Alessandra

AU - Bonanni, Bernardo

AU - Azzollini, Jacopo

AU - Manoukian, Siranoush

AU - Montagna, Marco

AU - Radice, Paolo

AU - Palli, Domenico

AU - Peterlongo, Paolo

AU - Ottini, Laura

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - BRCA1/2

KW - breast cancer risk

KW - genetic susceptibility

KW - male breast cancer

KW - MUTYH

KW - MUTYH-associated polyposis (MAP) syndrome

KW - NGS

U2 - 10.3389/fonc.2018.00583

DO - 10.3389/fonc.2018.00583

M3 - Article

VL - 8

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

ER -