PROSTATE cancer is the most commonly diagnosed internal malignancy in men, with its incidence rising sharply due to increasing life expectancy. While many prostate tumours remain indolent and do not require aggressive treatment, some exhibit aggressive behaviour, metastasising to distant sites and becoming lethal. Clinicians rely on clinico-pathological factors such as prostate-specific antigen (PSA) levels, tumour grade, and tumour size to assess disease severity. Among these, tumour grade – determined by the International Society of Urological Pathology (ISUP) Grade Group system – is the strongest predictor of localised disease lethality. ISUP Grade 1 tumours have minimal metastatic potential, whereas ISUP Grade 5 tumours are highly aggressive with poor prognosis.
The mechanisms driving variations in tumour grade remain unclear. Molecular studies have revealed that mutation density, particularly copy number aberrations (CNAs), and mRNA abundance subtypes correlate with tumour grade. Unlike other cancers, prostate tumours exhibit a relative paucity of coding point mutations, with no single mutation strongly correlating with grade. However, genetic factors play a significant role, accounting for approximately 57% of prostate cancer variability. Polygenic risk scores (PRS) derived from germline variants can predict prostate cancer risk and may indicate disease aggression. Additionally, rare germline mutations in DNA repair genes such as BRCA2 and transcription factors like HOXB13 have been linked to aggressive disease phenotypes.
Whole-genome sequencing (WGS) has further elucidated prostate cancer’s mutational landscape. A study of 666 localised prostate tumours identified 223 driver regions, many influenced by structural variations undetectable via targeted sequencing. Some of these driver mutations, including those in FOXA1, were significantly associated with high-grade cancers and worse clinical outcomes. Germline variants were found to influence the acquisition of specific somatic mutations, suggesting an interaction between inherited genetic factors and tumour evolution.
These findings support a model where prostate cancers of varying grades arise from a common evolutionary origin, with divergence influenced by early mutations, stochastic processes, and germline genetics. Importantly, differences in mutational patterns across ancestries underscore the need for diverse, multi-ethnic genomic studies to refine prognostic models and enhance personalised treatment strategies.
Katie Wright, EMJ
Reference
Yamaguchi TN et al. The germline and somatic origins of prostate cancer heterogeneity. Cancer Discov. 2025;DOI:10.1158/2159-8290.CD-23-0882.
