Health influenced by genetics: A first comprehensive analysis of breast cancer high and moderate penetrance susceptibility genes in the Tunisian population

Abstract

Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk score to predict breast cancer risk leading to better disease prevention and management.

Navigating the genetic landscape of breast cancer in South Africa amidst a developing healthcare system

“…Although this approach could infer ancestral haplotypes, it could not significantly associate novel rare variants with a rare, family-specific haplotype. As a next step, Boujemaa et al (2022) characterized the haplotypes of nine high and moderate-penetrance breast cancer susceptibility genes using SNPs from GWAS studies. Their study revealed distinct linkage disequilibrium patterns and identified putative functional SNPs that may be used to develop PRS.…”

“…Moving beyond variant prevalence, haplotype analysis using short tandem repeats (STRs) is the gold standard for confirming founder effects via segmented conservation (haploblocks) of the risk-associated loci. Given the inability of NGS to sequence repeats longer than the amplicon size, studies are increasingly using single nucleotide polymorphisms (SNPs) to infer haplotypes ( Tuazon et al, 2020 ; Boujemaa et al, 2022 ) through linkage disequilibrium analysis. Therefore, haplotype inference is becoming important for co-segregation analysis of variants of unknown clinical significance (VUS) or variants that may act as modifiers.…”

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

“…Breast cancer is the most prevalent cancer and the main cause of cancer-related mortality in women [191]. It may be inherited or linked to mutations in genes (BRCA1 and BRCA2, PTEN, TP53) involved in cellular proliferation, apoptosis, or other mitosis-related processes [192][193][194]. Apoptosis is particularly important for the healthy growth of the breast and the maintenance of homeostasis in the breast epithelial cell [195].…”

Association between a polymorphic variant in the CDKN2B‐AS1/ANRIL gene and pancreatic cancer risk

“…It has been observed that common, low‐penetrance genetic polymorphisms in or near genes harbouring high‐penetrance germline mutations are associated with the genetic susceptibility to develop cancer. For example, the CHEK2 and BRCA1 genes for breast cancer, 11 the TERT gene for melanoma, 12 the CDKN2A/2B genes for PDAC and pancreatic neuroendocrine tumours 13,14 and the p53 gene for multiple cancers have both high‐penetrance and low‐penetrance variants that contribute to the disease risk 15‐18 . Even though this phenomenon is not widespread, at least according to the current literature, exploring common variants in genes known to harbour high‐penetrance variants in PDAC could still be valuable for understanding the risk of developing PDAC.…”