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

Yosr Hamdi; Maroua Boujemaa; Najah Mighri; Nesrine Mejri; Olfa Jaidane; Sonia Ben Nasr; Hanen Bouaziz; Jamel Ben Hassouna; Aref Zribi; Yossra Berrazaga; Haifa Rachdi; Nouha Daoud; Houda El Benna; Soumaya Labidi; Abderrazek Haddaoui; Khaled Rahal; Farouk Benna; Hamouda Boussen; Sonia Abdelhak; Samir Boubaker

doi:10.3389/fgene.2021.674990

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

Front Genet. 2021 Aug 12:12:674990. doi: 10.3389/fgene.2021.674990. eCollection 2021.

Authors

Yosr Hamdi^{1

2}, Maroua Boujemaa¹, Najah Mighri¹, Nesrine Mejri^{1

3}, Olfa Jaidane⁴, Sonia Ben Nasr^{1

5}, Hanen Bouaziz^{1

4}, Jamel Ben Hassouna⁴, Aref Zribi⁵, Yossra Berrazaga³, Haifa Rachdi³, Nouha Daoud³, Houda El Benna³, Soumaya Labidi^{1

3}, Abderrazek Haddaoui⁵, Khaled Rahal⁴, Farouk Benna⁶, Hamouda Boussen^{1

3}, Sonia Abdelhak¹, Samir Boubaker^{1

2}

Affiliations

¹ Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.
² Laboratory of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis, Tunisia.
³ Medical Oncology Department, Abderrahmen Mami Hospital, Ariana, Tunisia.
⁴ Surgical Oncology Department, Salah Azaiez Institute of Cancer, Tunis, Tunisia.
⁵ Department of Medical Oncology, Military Hospital, Tunis, Tunisia.
⁶ Department of Radiation Oncology, University of Tunis, Tunis, Tunisia.

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.

Keywords: BRCA2 mutations; Cis double heterozygosity; breast cancer susceptibility; early age of onset; phenotype genotype correlation; whole exome sequencing.