BARD1 Pathogenic Variants are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort.

Paula Rofes,Orland Díez,Gabriel Capellá,Rafael De Cid,Joan Brunet,Judith Balmaña,Èlia Grau,Álex Teulé,Elisabet Munté,Conxi Lázaro,Adriana López-Doriga,Sara Torres-Esquius,Raquel Cuesta,Jesús Del Valle,Agostina Stradella,Judit Sanz,Olga Campos,José Marcos Moreno-Cabrera,Lídia Feliubadaló

doi:10.3390/genes12020150

Abstract

Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10–6.48; p = 1.16 × 10−5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10–7.70; p = 5.45 × 10−5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77–18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

Highlights

Hereditary breast and ovarian cancer (HBOC) risk has been traditionally linked to germline pathogenic variants (PVs) in breast cancer 1 and 2 genes (BRCA1 and BRCA2)
With the aim of investigating the role of PVs in the BRCA1-associated ring domain 1 (BARD1) gene, we performed an exhaustive analysis of truncating, splicing and Copy number variants (CNVs) in this gene
The remaining 18 BARD1mutated index patients tested negative for PVs in other breast cancer (BC)/OC genes

Summary

Introduction

Hereditary breast and ovarian cancer (HBOC) risk has been traditionally linked to germline pathogenic variants (PVs) in breast cancer 1 and 2 genes (BRCA1 and BRCA2). Several genes that are either interacting with BRCA1/2 or involved in DNA damage response pathways have emerged as potential candidates that may account for some of the missing heritability of these so-called BRCAX families, their associated risks have not been fully established [2]. BRCA1-associated ring domain 1 (BARD1) was first discovered in 1996 as the nuclear partner of BRCA1 and became one of the earliest candidates investigated [3]. It is localized on chromosome 2 at position 2q35 and encodes a protein of 777 amino acids that contains one N-terminal Really Interesting New Gene (RING)-finger domain, four Ankyrin (Ank) repeats and two C-terminal tandem BRCA1 C Terminus (BRCT) domains [4,5]. BARD1 is involved in other BRCA1-independent functions, including p53-mediated apoptosis [8]

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