Cancer Mutation in a Population of Middle Eastern Descent

Abstract

Breast cancer progression and development is driven through an intricate interaction of genetic and epigenetic influences. Current research on cancer in middle easten populations largely relies on targeted panels that focus on a predefined set of genes, which may limit the detection of broader genomic variations contributing to cancer susceptibility. Moreover, studies on DNA methylation as an epigenetic factor remain scarce in this region. This study addresses these gaps by employing an unbiased approach using whole exome sequencing to identify pathogenic, potentially pathogenic, and cancer-associated variants within the United Arab Emirates population—a demographic previously underepresented in cancer research. Additionally, the study investigates DNA methylation profiles to assess the extent of differential methylation patterns, providing a comprehensive insight into both genetic and epigenetic contributions to breast cancer withinn this population. The genetic study includes 94 breast cancer samples and 72 controls that showed a total of 23,212 variants in cases predominantly ATR and CHEK2 as pathogenic mutations, ALK, CDKN1B and SDHA as potentially pathogenic mutations and TSC1, POLE and MSH2 as cancer-associated mutations. GAGE analysis showed the top-upregulated pathways relating to protein degradation, cell cycle, cell division and protein stability. The epigenetic study includes 93 breast cancer samples which were normalized and set for batch correction showing hypermethylation predominance in CpG island and shore. Gene enrichment analysis showed the hypermethyaltion of CpG sites in CDKN2B, HOXB13 and BRCA2 and hypomethylation of PRF1, and key genes shown to be differentially methylated are WT1, MSH6, SLX4, PTEN, BRCA2 and ATM. Pathway enrichment identified key biological processes to be immune response, inflammation, apotosis regulation and cell death. Laying the groundwork for future in-depth cancer genetic and epigenetic research, this study highlights that the distinctive genetic and epigenetic composition of underrepresented groups influences the penetrance and manifestation of genes that could contribute to hereditary cancer risk in ways that diverge from patterns observed in more extensively researched cohorts.

Date of Award	28 Nov 2024
Original language	American English
Supervisor	Habiba Alsafar (Supervisor)