Ancestry-specific predisposing germline variants in cancer

Area of Science:

• Genomics
• Cancer Research
• Population Genetics

Background:

• Cancer risk and genetic predisposition show distinct prevalence across different ancestries.
• Germline genome analyses specific to ancestry are essential for understanding cancer genetic risk and prognosis in diverse populations.

Purpose of the Study:

• To analyze the association between cancer predisposition genes (CPGs) and cancer types within ancestral groups using The Cancer Genome Atlas (TCGA) data.
• To identify ancestry-specific genetic variants, two-hit events, and gene expression effects in tumors.

Main Methods:

• Germline and somatic sequencing data from TCGA were analyzed.
• Pathogenic and likely pathogenic variants were collapsed into CPGs.
• Association analyses were performed within ancestral groups, including African, East Asian, and European ancestries.

Main Results:

• A novel association of BRCA2 with lung squamous cell carcinoma was discovered in individuals of African ancestry.
• A known association of BRIP1 with stomach adenocarcinoma was identified in East Asian ancestry.
• Most predisposing variants were found to be ancestry-specific, with loss of heterozygosity observed in African ancestry carriers.

Conclusions:

• While some CPGs are shared, many pathogenic variants are ancestry-specific and influence somatic effects.
• Larger, diverse cohorts are needed to identify all ancestry-specific genetic predispositions.
• Findings can inform the development of tailored genetic screening strategies for diverse populations.