Aims: Kataegis, describing focal DNA hypermutations, has been observed in multiple types of cancer genomes with highly inflated genomic instability that has been tentatively correlated with disease aggression and/or relapse in prostate cancer. Men of African ancestry are at greatest risk for advanced disease presentation, with tumours derived from men from sub-Saharan Africa recently have shown to harbour a considerably elevated level of acquired genomic variation. However, kataegis events linked to adverse outcomes associated with ancestral-driven prostate cancer health disparities remains unexplored. Here we aim to identify the kataegis from African and European patients with prostate cancer and assess its associations with elevated genomic aberrations and outcomes.
Methods: Kataegis was identified with piecewise constant fitting model leveraging whole genome sequencing data from 112 African and 57 European patients. Wilcoxon rank-sum test was conducted for statistical analysis using clinical and genomic data obtained from Jaratlerdsiri et al., 2021. Results of multiple tests were adjusted with false discovery rate (FDR).
Results: We identified a total of 238 kataegis loci carried by 66 patients. In African patients, larger and more kataegis loci were observed in high-risk (31 out of 83, median three loci, 5 kb) than low-risk (10 out of 29, median, 1 locus, 0.74 kb (p-values =0.033, 0.019, respectively). Kataegis positive was associated with PSA in high-risk patients (FDR = 0.005). In European patients, higher incidences of kataegis were observed in high-risk (25 out of 50 versus 0 out of 7, p-value = 0.033) and was linked to worse clinical outcome (p-value=0.006).
African kataegis showed a deviation from known features. Only certain types of genomic rearrangements (chromothripsis, duplication, and deletion) were enriched within 10 kb of kataegis in high-risk African patients as opposed to all types enriched for European patients. Evolutionary timing analysis showed that kataegis occurred later in high-risk African patients than in Europeans. Additionally, flanking sequences of kataegis in low-risk African patients indicate an unknown aetiology other than APOBEC family activity
Discussion: We showed the link between kataegis and cancer aggressiveness. Compared to European patients, kataegis demonstrated divergent features in African patients, which indicates a more complicated mutational process undermining the cancer development. Low-risk African patients with kataegis positive may have a higher risk of progression.
Conclusion: While kataegis is a relatively unexplored phenomenon in prostate cancer, this study provides the first evidence that different mechanisms may be driving this type of genomic instability in men from different ancestries.