Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia.

Mohamed Samir Boubaker,Khaled Rahal,Abderrazek Haddaoui,Lilia Romdhane,Maroua Boujemaa,Kais Ghedira,Soumaya Labidi,Nesrine Mejri,Sonia Ben Nasr,Sonia Abdelhak,Hanen Bouaziz,Houda El Benna,Yosr Hamdi,Olfa Jaidane,Hamouda Boussen,Hamza Dallali

doi:10.1371/journal.pone.0245362

Abstract

Hereditary breast cancer accounts for 5–10% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in BRCA1/2 genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9 BRCA negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes.

Highlights

Breast cancer is the most common malignancy in women worldwide with approximately 2.09 million new cases diagnosed per year [1]
We investigated the biological and functional features of genes contained within Copy number variations (CNVs) classified as likely pathogenic and pathogenic using different online databases: 1) Network of Cancer Genes version 6.0 to identify genes associated with malignancy [35], 2) Web-based Gene Set Analysis Toolkit V2 (WebGestalt2) to reveal common functions of the gene products [36], 3) Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper–Search Disease tool for searching disease genes in the KEGG DISEASE database [37], 4) The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 which provides a comprehensive set of functional annotation tools for investigators to understand biological meaning behind large list of genes and to identify genomic loci associated with genetic disorders including cancer [38]
We performed whole exome sequencing for 9 BRCA negative breast cancer cases and 10 matched controls with the aim to assess the contribution of germline CNVs to hereditary breast cancer in the Tunisian population

Summary

Introduction

Breast cancer is the most common malignancy in women worldwide with approximately 2.09 million new cases diagnosed per year [1]. It is estimated that 5–10% of all breast cancers are hereditary cases [2, 3]. Gene re-sequencing as well as genome wide association studies allowed the identification of high, moderate and low penetrant variants that collectively explained only half of the breast cancer genetic component [3, 4]. The genetic background of a substantial part of hereditary cases are yet to be discovered. Copy number variations (CNVs), typically defined as a gain or a loss of DNA sequences larger than 50 bp compared to a reference genome [5], might contribute to the remaining genetic basis of breast cancer risk [6]. Several CNVs have already been identified as associated with many diseases including complex disorders such as cancer [7]. Deleterious CNVs in cancer patients have been observed in more than 30% of highly penetrant cancer-predisposing genes, including BRCA1, BRCA2, APC, as well as mismatch repair (MMR) genes [7, 8]

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