Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases

Abstract

BackgroundA family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking.MethodsA whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein–protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk.ResultsSequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein–protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6.ConclusionsIn this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1504-9) contains supplementary material, which is available to authorized users.

CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer

“…For the c.-176C > T variant, no information published about their impact or functionality on CDH1 gene expression. The variants c.2164 + 17dupA and c.2439 + 52G > A, alters exonic splicing sites (ESS and ESE), the c.2164 + 17dupA is a common non-coding variant observed in 13/20 patients in our study, it is considered as benign by ClinVar, also, it was found in patients with breast cancer but was considered as no pathogenic [20]). On the other hand, the c.2439 + 52G > A variant was observed in our study only in one patient, the clinical significance information is not yet reported in ClinVar, so in both cases the functional role need be clarified in future research.…”

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

“…BARD1 isoforms caused by genetic mutations or SNPs are upregulated in many tumors [ 13 , 14 , 18 , 96 , 122 ]. Interestingly, few of the genetic mutations discussed here are present in and influence the risk of developing breast and gynecological cancers, suggesting that some of these BARD1 SNPs may be cancer-specific ( Supplementary Tables S1 and S2 ) [ 19 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 ]. Whether BARD1 variants are secondary to treatment or part of the oncogenic progression has not been fully elucidated.…”

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

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