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Prevalence of germline variants in consensus moderate-to-high-risk predisposition genes to hereditary breast and ovarian cancer in BRCA1/2-negative Brazilian patients

  • Epidemiology
  • Published:
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Abstract

Purpose

This study aimed to identify and classify genetic variants in consensus moderate-to-high-risk predisposition genes associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC), in BRCA1/2-negative patients from Brazil.

Methods

The study comprised 126 index patients who met NCCN clinical criteria and tested negative for all coding exons and intronic flanking regions of BRCA1/2 genes. Multiplex PCR-based assays were designed to cover the complete coding regions and flanking splicing sites of six genes implicated in HBOC. Sequencing was performed on HiSeq2500 Genome Analyzer.

Results

Overall, we identified 488 unique variants. We identified five patients (3.97%) that harbored pathogenic or likely pathogenic variants in four genes: ATM (1), CHEK2 (2), PALB2 (1), and TP53 (1). One hundred and thirty variants were classified as variants of uncertain significance (VUS), 10 of which were predicted to disrupt mRNA splicing (seven non-coding variants and three coding variants), while other six missense VUS were classified as probably damaging by prediction algorithms.

Conclusion

A detailed mutational profile of non-BRCA genes is still being described in Brazil. In this study, we contributed to filling this gap, by providing important data on the diversity of genetic variants in a Brazilian high-risk patient cohort. ATM, CHEK2, PALB2 and TP53 are well established as HBOC predisposition genes, and the identification of deleterious variants in such actionable genes contributes to clinical management of probands and relatives.

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Acknowledgements

We are very thankful to all patients who participated in this study. We also thank Kelly Rose Lobo de Souza who performed BRCA genetic testing and Carolina Furtado for her experimental assistance. This work was supported by the National Institute for Cancer Control (INCT para Controle do Câncer; https://www.inct-cancer-control.com.br), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil, Grant Numbers: 305873/2014-8 and 573806/2008-0), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil Grant Number: E26/170.026/2008). PSS was supported by grants from the Rio de Janeiro State Science Foundation (FAPERJ E26/201.200/2014), the Brazilian National Research Council (CNPq 304498/2014-9), and the Coordination for Higher Education Personnel Training (CAPES). This study is part of the requirements for the doctoral degree in Genetics of PSS at the Federal University of Rio de Janeiro.

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  1. Renan Gomes and Pricila da Silva Spinola: These authors contributed equally.

Authors and Affiliations

  1. Genetics Program, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil

    Renan Gomes, Ayslan Castro Brant, Bruna Palma Matta, Silvia Maria de Aquino Paes, Cibele Rodrigues Bonvicino, Anna Claudia Evangelista dos Santos & Miguel Angelo Martins Moreira

  2. Programa de Pós-Graduação em Genética, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil

    Pricila da Silva Spinola & Caroline Macedo Nascimento

  3. Instituto Federal do Rio de Janeiro (IFRJ), Rio de Janeiro, Brazil

    Silvia Maria de Aquino Paes

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Contributions

Study conception and design: MAMM and CRB. Patients’ inclusion, clinical data collection, and Genetic Counseling: ACES. DNA sequencing: RG, PSS, CMN, SMAP and BPM. Identification of genetics variants and pathogenicity classification: RG, ACB, PSS, and BPM. Manuscript writing—original draft: RG. Manuscript writing—review and editing: RG, PSS, BPM, and MAMM. Funding acquisition: MAMM and CRB. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Miguel Angelo Martins Moreira.

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Conflict of interest

The authors declare that they have no conflict of interest.

Patient consent

All individuals who participate in this study provided written informed consent approved by the local ethics committee. No identifiable personal patient data are show in this article.

Research involving human rights

All procedures performed in studies involving human participants were approved by the ethical committee of the Brazilian National Cancer Institute (INCA; Project #114/07 and C.A.A.E. 14144819.0.0000.5274).

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Supplementary file1 Supplementary Fig. 1 Overview of the germline variants found in this study (EPS 1466 kb)

10549_2020_5985_MOESM2_ESM.eps

Supplementary file2 Supplementary Fig. 2 Pathogenic (P), likely pathogenic (LP), and VUS classified as probably damaging by protein position. Protein domains are shown as colored bars (EPS 3033 kb)

Supplementary file3 (DOC 337 kb)

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Gomes, R., Spinola, P.d., Brant, A.C. et al. Prevalence of germline variants in consensus moderate-to-high-risk predisposition genes to hereditary breast and ovarian cancer in BRCA1/2-negative Brazilian patients. Breast Cancer Res Treat 185, 851–861 (2021). https://doi.org/10.1007/s10549-020-05985-9

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