Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients.

Rebeca Silveira Grasel,Pedro De Marchi,Paula Silva Felicio,Giovana Tardin Torrezan,Edilene Santos De Andrade,Gabriela Carvalho Fernandes,André Escremim De Paula,Cristina Da Silva Sabato,Cláudia Alessandra Andrade De Paula,Henrique De Campos Reis Galvão,Felipe Antônio De Oliveira Garcia,Cristiano De Pádua Souza,Adriane Feijó Evangelista,Edenir Inêz Palmero,Natalia Campacci,Dirce Maria Carraro

doi:10.3389/fonc.2020.571330

Rebeca Silveira Grasel, Pedro De Marchi + Show 14 more

Open Access

https://doi.org/10.3389/fonc.2020.571330

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Abstract

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for BRCA1/BRCA2 pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the ATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, and RAD51C genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the BRIP1 gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATM c.4709T>C; CHEK2 c.1036C>T; PALB2 c.1001A>G, and RAD50 c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.

Highlights

Germline pathogenic BRCA1 or BRCA2 variants are responsible for ∼15–25% of the hereditary breast/ovarian cancer (HBOC) cases [1, 2]
A retrospective cohort study of 52 unrelated women over 18 years of age with a personal and/or family history (FH) suggestive of HBOC were included. These women were referred to the Department of Cancer Genetics of the Barretos Cancer Hospital (BCH) and tested negative for pathogenic germline variants of the BRCA1, BRCA2, and TP53 genes [as described by Fernandes et al [8]]
Of the 52 unrelated women with a personal and family history suggestive of breast and/or ovarian cancer, two pathogenic germline variants and germline variants of uncertain significance (VUS) were identified through the use of a gene panel containing genes associated with highand moderate-risks of breast and ovarian cancer

Summary

Introduction

Germline pathogenic BRCA1 or BRCA2 variants are responsible for ∼15–25% of the hereditary breast/ovarian cancer (HBOC) cases [1, 2]. Other than BRCA1/BRCA2, several high and moderate cancer genes have been associated with HBOC. The wide use of gene panels has proven to be extremely useful in clinical practice due to the optimization of both time and cost, and to the identification and monitoring of high-risk families for hereditary breast cancer, harboring pathogenic germline variants in genes other than BRCA1 and BRCA2. It is worth noting that co-segregation and loss of heterozygosity analysis have been widely used and have an important role in the classification of variants of tumor suppressor genes identified in high risk families [4,5,6,7]

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