Poster Presentation 46th Lorne Genome Conference 2025

Kataegis associated mutational processes linked to adverse prostate cancer presentation and ethnic disparities   (#163)

Jue Jiang 1 , Avraam Tapinos 2 , Ruotian Huang 1 , M.S. Riana Bornman 3 , Phillip D. Stricker 4 , Shingai B. A. Mutambirwa 5 , David C. Wedge 2 , Weerachai Jaratlerdsiri 1 , Vanessa M. Hayes 1 2 3
  1. Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  2. Manchester Cancer Research Centre, University of Manchester, Manchester, UK
  3. School of Health Systems & Public Health, University of Pretoria, Pretoria, South Africa
  4. St Vincent's Prostate Cancer Research Centre, Sydney, NSW, Australia
  5. Department of Urology, Sefako Makgatho Health Science University, Dr George Mukhari Academic Hospital, Ga-Rankuwa, South Africa

Background

Kataegis, the focal hypermutation of single base substitutions in tumour genomes, has received little attention with respect to prostate cancer (PCa) molecular features, clinical outcomes, as well as racial disparities between ethnic groups. Most notably, its knowledge in tumour biology is absent among African men disproportionately impacted by prostate cancer.

Results

Here through comparison between African (n = 109) and European (n = 57) whole genome sequenced treatment naïve primary prostate tumours, using a single analytical workflow we assessed for ethnic- shared and unique features of kataegis. While PCa patients are of light burden of small kataegis as observed in patients regardless of ancestry, kataegis positives showed association with modular features of genomic instability, and co-occurrence with point mutations of cancer drivers (FDR = 3e-6 – 0.04). What’s more, kataegis are linked to adverse clinical outcome, marked by higher prostate-specific antigen (PSA) value in African patients (FDR = 0.04) and susceptible to metastasis shown in the European validation cohort (P-value = 0.009). While kataegis mainly attributed to APOBEC enzyme activity, the proportion showed relativeness to cancer aggressiveness in African patients. Further analysis on evolutionary timing and proximal SVs of kataegis revealed ethnical-unique features. While European patients were predominantly presented with kataegis in clonal epoch closed to structural variants (SV), African patients were presented with more kataegis raised in subclones, and positioned independently to SVs, most noticeably for translocations and translocation inversions.

Conclusions

These results suggest a heightened kataegis-induced genomic instability during prostate tumourigenesis among African patients, which supports the significance of a continued exploration of biological behaviours and environmental carcinogens for African patients.