Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer

Giovana T Torrezan,Sandro J De Souza,Cláudia A A De Paula,Amanda F De Nóbrega,Edenir I Palmero,Elisa N Ferreira,Fernanda G Dos Santos R De Almeida,Maria I Achatz,Márcia C P Figueiredo,Felipe C C Da Silva,Bruna D De Figueiredo Barros,Renan Valieris,Paula S Felicio,Jorge E S De Souza,Rodrigo F Ramalho,Dirce M Carraro

doi:10.3389/fgene.2018.00161

Abstract

Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations.

Highlights

Hereditary breast cancer (HBC) corresponds to ∼5–10% of all breast cancer cases (Honrado et al, 2005)
The use of whole-exome sequencing (WES) in clinical genetics has been proven to be an effective alternative for establishing the genetic basis of Mendelian diseases, in diseases where multiple genes can be affected (Trujillano et al, 2016)
In both clinical and research settings, WES has been applied to elucidate the genetic cause of cancer predisposition

Summary

Introduction

Hereditary breast cancer (HBC) corresponds to ∼5–10% of all breast cancer cases (Honrado et al, 2005). The most common breast cancer predisposing syndrome is hereditary breast and ovarian cancer syndrome (HBOC) that is related to pathogenic germline variants in BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) genes (Anglian Breast Cancer Study, 2000). These genes correspond to ∼20–25% of all HBC (Anglian Breast Cancer Study, 2000; Kean, 2014; Silva et al, 2014). Over 35 genes have been suggested to carry high and/or moderate BC risk variants (OMIM, 20151; Shiovitz and Korde, 2015). Despite extensive sequencing efforts, variants in known BC susceptibility genes are present in < 30% of BC cases with positive family history or an early age of onset (Shiovitz and Korde, 2015; Chandler et al, 2016), meaning that the underlying genetic factors for most HBC remain unknown

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