Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology.

Yosr Hamdi,Yossra Berrazaga,Sonia Abdelhak,Houda El Benna,Nouha Daoud,Samir Boubaker,Maroua Boujemaa,Nesrine Mejri,Najah Mighri,Hanen Bouaziz,Jamel Ben Hassouna,Soumaya Labidi,Hamouda Boussen,Khaled Rahal,Haifa Rachdi,Olfa Jaïdane ,A Haddaoui ,S Ben Nasr ,A Zribi ,F Benna

doi:10.3389/fgene.2021.674990

Abstract

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

Highlights

Breast cancer is the most common malignancy in women worldwide (Rojas and Stuckey, 2016)
We aimed to present a first report on a BRCA2 Cis double heterozygosity in 5 Tunisian families thanks to the use of whole exome sequencing
Tunisian families from different geographic origins were selected based on the following selection criteria; (1) having at least 3 breast cancer cases in first or second degree relatives at any age, (2) 2 breast cancer cases with one of them diagnosed with Breast cancer (BC) before age 40, (3) isolated breast cancer cases diagnosed before age 36, (4) one case with triple negative breast cancer (TNBC) at an age ≤40 years, (5) one case and one ovarian case diagnosed at first or second degree relatives at any age, (6) at least 2 cases with breast or ovarian cancer and at least one case with pancreas cancer or prostate cancer at first or second degree relatives

Summary

Introduction

Breast cancer is the most common malignancy in women worldwide (Rojas and Stuckey, 2016). Incidence and mortality rates of breast cancer differ between populations (Bray et al, 2018). About 1,800 mutations have been identified on BRCA1 and almost 2,000 mutations on BRCA2 (Szabo et al, 2000). These mutations explain around 20–30% of hereditary breast cancer cases and seem to be associated with different other cancers such as ovarian, prostate, colorectal, pancreatic, and melanoma (Mehrgou and Akouchekian, 2016). The identification of a BRCA mutation can lead to risk or mortality reduction if optimal surveillance, risk-reducing mastectomy, and riskreducing salpingo-oophorectomy are applied (Finch et al, 2006; Domchek et al, 2010). Cancer treatment of BRCA mutation carriers has advanced with the development of PARP inhibitors, which take advantage of the loss of BRCA1/2 function in tumors (Farmer et al, 2005)

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