Cancer Susceptibility Genes in Saudis

Genetic predisposition plays an important role in cancer initiation and progression, especially in homogenous populations with high consanguinity (~60%) like in Saudi Arabia. With a predominantly young population, this may potentially increase the burden of recessive/dominant cancer syndromes. Genomic databases offer an opportunity to identify the genetic risk background, define high risk subgroups, and optimize screening and intervention. Regional data are lacking, particularly in the Middle Eastern populations with unique genetic architectures. This study aims to estimate the prevalence of pathogenic/likely pathogenic (P/LP) and variants of unknown significance (VUS) in common cancer-associated genes (e.g., TP53, BRACA1, BRACA2, RET, PTEN, APC, DICER1, SDHx) among Saudi patients using a large genomic data repository. By analyzing whole-exome linked to electronic health records (EHR), we will:

1. Identify carriers of P/LP/VUS variants in known cancer-associated genes in a Saudi cohort.

2. Calculate syndrome-specific prevalence and compare it to global estimates.

3. Assess clinical penetrance (cancer diagnosis rates among variant carriers).

4. Explore demographic/clinical correlates (age, sex, cancer subtype, family history).

5. Develop recommendations for genetic testing and surveillance in high-risk Saudi population.

Our central hypothesis is that the prevalence of cancer-associated P/LP/VUS variants in Saudi Arabia is high and differs from global estimates, due to unique genetic and environmental factors. The study will leverage existing genomic databases at King Faisal Specialist Hospital & Research Centre (KFSHRC), adhering to ethical guidelines for secondary data use. Findings will inform genetic testing guidelines and enhance early detection strategies for hereditary cancer in Saudi Arabia and the region. It will also assess the Saudi population genetic predisposition index for common cancers.