Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene

Valentina Silvestri, Veronica Zelli, Virginia Valentini, Piera Rizzolo, Anna Sara Navazio, Anna Coppa, Simona Agata, Cristina Oliani, Daniela Barana, Tiziana Castrignanò, Alessandra Viel, Antonio Russo, Maria Grazia Tibiletti, Ines Zanna, Giovanna Masala, Laura Cortesi, Siranoush Manoukian, Jacopo Azzollini, Bernard Gilles Peissel, Bernardo Bonanni & 7 others Paolo Peterlongo, Paolo Radice, Domenico Palli, Giuseppe Giannini, G. Chillemi, Marco Montagna, Laura Ottini

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases.

Original languageEnglish
JournalCancer
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Male Breast Neoplasms
Exome
Neoplasm Genes
Genes
Mutation
Breast Neoplasms
Nonsense Codon
Pedigree
Genetic Predisposition to Disease
Rare Diseases
Germ Cells
Fathers
Multicenter Studies

Keywords

  • Genetic susceptibility
  • Male breast cancer
  • N-acetyltransferase 1 (NAT1)
  • Partner and localizer of BRCA2 (PALB2)
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Silvestri, V., Zelli, V., Valentini, V., Rizzolo, P., Navazio, A. S., Coppa, A., ... Ottini, L. (Accepted/In press). Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. Cancer. https://doi.org/10.1002/cncr.30337

Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. / Silvestri, Valentina; Zelli, Veronica; Valentini, Virginia; Rizzolo, Piera; Navazio, Anna Sara; Coppa, Anna; Agata, Simona; Oliani, Cristina; Barana, Daniela; Castrignanò, Tiziana; Viel, Alessandra; Russo, Antonio; Tibiletti, Maria Grazia; Zanna, Ines; Masala, Giovanna; Cortesi, Laura; Manoukian, Siranoush; Azzollini, Jacopo; Peissel, Bernard Gilles; Bonanni, Bernardo; Peterlongo, Paolo; Radice, Paolo; Palli, Domenico; Giannini, Giuseppe; Chillemi, G.; Montagna, Marco; Ottini, Laura.

In: Cancer, 2016.

Research output: Contribution to journalArticle

Silvestri, V, Zelli, V, Valentini, V, Rizzolo, P, Navazio, AS, Coppa, A, Agata, S, Oliani, C, Barana, D, Castrignanò, T, Viel, A, Russo, A, Tibiletti, MG, Zanna, I, Masala, G, Cortesi, L, Manoukian, S, Azzollini, J, Peissel, BG, Bonanni, B, Peterlongo, P, Radice, P, Palli, D, Giannini, G, Chillemi, G, Montagna, M & Ottini, L 2016, 'Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene', Cancer. https://doi.org/10.1002/cncr.30337
Silvestri, Valentina ; Zelli, Veronica ; Valentini, Virginia ; Rizzolo, Piera ; Navazio, Anna Sara ; Coppa, Anna ; Agata, Simona ; Oliani, Cristina ; Barana, Daniela ; Castrignanò, Tiziana ; Viel, Alessandra ; Russo, Antonio ; Tibiletti, Maria Grazia ; Zanna, Ines ; Masala, Giovanna ; Cortesi, Laura ; Manoukian, Siranoush ; Azzollini, Jacopo ; Peissel, Bernard Gilles ; Bonanni, Bernardo ; Peterlongo, Paolo ; Radice, Paolo ; Palli, Domenico ; Giannini, Giuseppe ; Chillemi, G. ; Montagna, Marco ; Ottini, Laura. / Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. In: Cancer. 2016.
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title = "Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene",
abstract = "BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10{\%} of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases.",
keywords = "Genetic susceptibility, Male breast cancer, N-acetyltransferase 1 (NAT1), Partner and localizer of BRCA2 (PALB2), Whole-exome sequencing",
author = "Valentina Silvestri and Veronica Zelli and Virginia Valentini and Piera Rizzolo and Navazio, {Anna Sara} and Anna Coppa and Simona Agata and Cristina Oliani and Daniela Barana and Tiziana Castrignan{\`o} and Alessandra Viel and Antonio Russo and Tibiletti, {Maria Grazia} and Ines Zanna and Giovanna Masala and Laura Cortesi and Siranoush Manoukian and Jacopo Azzollini and Peissel, {Bernard Gilles} and Bernardo Bonanni and Paolo Peterlongo and Paolo Radice and Domenico Palli and Giuseppe Giannini and G. Chillemi and Marco Montagna and Laura Ottini",
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issn = "0008-543X",
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T1 - Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene

AU - Silvestri, Valentina

AU - Zelli, Veronica

AU - Valentini, Virginia

AU - Rizzolo, Piera

AU - Navazio, Anna Sara

AU - Coppa, Anna

AU - Agata, Simona

AU - Oliani, Cristina

AU - Barana, Daniela

AU - Castrignanò, Tiziana

AU - Viel, Alessandra

AU - Russo, Antonio

AU - Tibiletti, Maria Grazia

AU - Zanna, Ines

AU - Masala, Giovanna

AU - Cortesi, Laura

AU - Manoukian, Siranoush

AU - Azzollini, Jacopo

AU - Peissel, Bernard Gilles

AU - Bonanni, Bernardo

AU - Peterlongo, Paolo

AU - Radice, Paolo

AU - Palli, Domenico

AU - Giannini, Giuseppe

AU - Chillemi, G.

AU - Montagna, Marco

AU - Ottini, Laura

PY - 2016

Y1 - 2016

N2 - BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases.

AB - BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases.

KW - Genetic susceptibility

KW - Male breast cancer

KW - N-acetyltransferase 1 (NAT1)

KW - Partner and localizer of BRCA2 (PALB2)

KW - Whole-exome sequencing

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DO - 10.1002/cncr.30337

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