Investigating the contribution of germline and somatic variants in the fatty acid metabolism pathway to prostate cancer aggressiveness in Southern African men

Abstract

Prostate cancer (PCa) is a significant global health issue, ranking second in cancer diagnoses and is the fifth leading cause of cancer-related deaths among men worldwide. Men of African ancestry have disproportionately higher PCa-associated mortality rates compared to other racial groups, underscoring a critical health disparity that necessitates further research. Despite this, most PCa genome studies focus predominantly on populations of European ancestry, excluding African men from tailored diagnosis and treatment options. PCa progression is facilitated by altering various signalling and metabolic pathways including fatty acid metabolism (FAM). To support their rapid growth, PCa cells meet their higher energy demands primarily through the oxidative degradation of fatty acids. While genes involved in FAM have been extensively studied, it is not well understood how both germline and somatic mutations within FAM influence patient predisposition and PCa progression. This project sought to address this gap by investigating the impact of germline and somatic variants within the FAM pathway on PCa aggressiveness in men of African and European ancestry. Data generated from the Southern African Prostate Cancer Study (SAPCS) was used in this study. A total of 743 Black South African men participating in the SAPCS underwent whole-exome genotyping. Common variants (MAF > 0.01) in 158 FAM genes were tested for association with PCa (451 cases vs 292 controls) and PCa aggressiveness (203 high risk, ISUP 3-5, vs 461 low risk, ISUP 1-2 and controls) using logistic regression. The significant variants were assessed for deleterious or damaging effects using SIFT and PolyPhen. Rare germline and somatic variant analysis were performed on whole-genome sequencing data from 158 treatment-naive individuals with PCa (Australia: n=53; South Africa: n=105). Rare variants (MAF < 0.05) were annotated with ANNOVAR, ClinVar, InterVar, and cancer genome interpreter as well as functional impact prediction tools (SIFT, PolyPhen, CADD, LOFTEE). The somatic variants were assessed for deleteriousness using SIFT and PolyPhen and tumour mutational burden (TMB) of the somatic variants was calculated. Nine common SNPs in FAM-related genes were significantly associated with PCa, including three deleterious variants in . Eight SNPs were linked to aggressive PCa, with deleterious variants in INMT and AOC3. These common SNPs had not been previously associated with PCa. Rare germline analysis revealed 15 pathogenic variants, four oncogenic variants and 15 variants with predicted loss of function. 80% of individuals with these rare variants had aggressive PCa. Somatic analysis showed African tumours had a higher (though not statistically significant) mean TMB than European tumours ( ). Several PDVs were exclusive to African-derived tumours, including mutations in FASN, ACADL, ACOT8, and ADH1C. Although limited by a small sample size, this study reveals novel germline and somatic variants in FAM pathway genes, highlighting their contribution to PCa risk and aggressiveness. Future research should prioritise African population inclusion, increased sample size, and include phenotypic studies in PCa genomics to improve diagnostics, treatment, and health equity.