Loading...
EXPLORING THE BREAST CANCER GERMLINE AND SOMATIC MUTATIONS LANDSCAPE IN QATAR
Citations
Altmetric:
Video URL
Date
2026-06
Author
Collections
Files
Lama Abujamous__OGS Approved Dissertation.pdf
Adobe PDF, 4.24 MB
- Available to administrators
Abstract
Breast cancer represents a significant public health and clinical challenge in the Middle East and North Africa (MENA) region. It is characterized by an earlier age at diagnosis, heterogeneous tumor features, and underrepresentation in global genomic databases. These factors hinder accurate risk assessment, variant interpretation, and the implementation of precision oncology. This dissertation addresses these gaps by conducting an integrated, population-specific investigation of breast cancer genomics and associated risk factors in Qatar within the broader MENA context. This dissertation consists of five complementary components. First, a PRISMA-guided systematic review of somatic mutations reported in MENA breast cancer is conducted. Second, somatic mutation profiling of a Qatar breast cancer cohort is performed using whole-exome sequencing and a tumour-only workflow. Third, BRCA1 variants of uncertain significance are reinterpreted employing ACMG/AMP criteria, BRCA1-specific specifications, Bayesian scoring, and ancestry-matched allele-frequency data. Fourth, germline variants in breast cancer predisposition genes are evaluated using Qatar Genome Program data within a case-control framework. Fifth, phenotypic predictors of breast cancer are examined using data from the Qatar Biobank and Qatar Genome Program. The systematic review identified 559 curated somatic variants across 104 genes from 44 eligible studies in 13 MENA countries, revealing recurrent involvement of canonical breast cancer drivers, particularly TP53 and PIK3CA, despite substantial heterogeneity in study design, sequencing scope, and reporting practices. Somatic analysis of the Qatar cohort indicated that invasive ductal carcinoma was the predominant histological subtype, and that triple-negative breast cancer constituted a significant proportion of cases, reflecting a clinically important aggressive disease spectrum. The BRCA1 reinterpretation analysis demonstrated that incorporating ancestry-aware frequency data and gene-specific interpretation frameworks reduces avoidable uncertainty and improves classification accuracy in underrepresented populations. Germline analysis identified a limited but clinically meaningful subset of inherited variants while confirming that many rare variants remain appropriately classified as variants of uncertain significance pending stronger evidence. Phenotype analysis revealed that age was the primary predictor of case-control separation, although selected metabolic correlates persisted after adjusting for confounding variables. Collectively, these findings support a Qatar-relevant precision medicine framework based on standardized tumor profiling, rigorous germline interpretation utilizing national genomic resources, and phenotype-informed risk modelling.