Genomic analysis identifies mutational footprints in prostate cancer

Researchers have identified eight integrated mutational footprints (IMFs) that explain the mutational processes in 85% of primary prostate cancer genomes. The study, which analyzed whole-genome sequencing data from 959 primary prostate cancer samples, aims to clarify the causes behind the disease's clinical heterogeneity, ranging from indolent to highly lethal forms.

By integrating various signature modalities—including single-base substitutions, insertion–deletions, copy number variants, and complex structural variants—the team mapped the biological processes driving these genetic alterations. Key drivers identified include androgen receptor-mediated mutagenesis and replication stress.

Four of these IMFs were significantly associated with a shorter time to metastasis. These include reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency. Notably, the latter was found to be enriched in patients of African ancestry. Additionally, the IMFs showed potential in predicting sensitivity to androgen receptor pathway inhibitors, offering a framework for improved risk stratification and biomarker-guided treatment selection.