Reading the DNA Fingerprints of Prostate Cancer

Prostate cancer does not develop in the same way in every patient. Different biological processes can damage the DNA of cancer cells, leaving behind characteristic patterns, or “mutational signatures.” A recent study, published on Nature, used whole-genome sequencing to combine these patterns and identify eight integrated mutational footprints (IMFs), providing a broader picture of how prostate cancer develops and behaves.

The researchers considered several types of genomic alterations: single-base substitutions (SBS), small insertions and deletions (indels), copy-number alterations, and structural variants. Rather than analysing these changes separately, they looked at how they occurred together. This allowed them to group related patterns into eight IMFs, each reflecting a different underlying biological process.

The main processes identified included mismatch-repair deficiency, oxidative or reactive oxygen species (ROS) damage, androgen receptor (AR) activity, replication stress, APOBEC activity, and homologous recombination (HR) deficiency. HR deficiency appeared in two different forms: one strongly associated with BRCA2 alterations and another associated with CDK12 alterations. Overall, these footprints explained the mutational processes in around 85% of primary prostate cancers studied.

The 8 IMFs in simple language

The study also examined whether these genomic patterns were related to clinical characteristics. The researchers considered factors including age, tumour stage, Gleason grade, tumour mutational burden, risk of metastasis, and treatment response. Four IMFs, those linked to ROS damage, AR activity, non-canonical HR deficiency and canonical HR deficiency, were associated with a higher risk of metastasis, even after accounting for several standard clinical and genomic factors.

Treatment response was another important parameter. In patients with metastatic prostate cancer, the researchers compared outcomes between androgen receptor pathway inhibitors (ARPIs) and taxane chemotherapy. Tumours with high levels of IMF6, which represents replication stress, appeared to respond better to ARPIs than to taxanes. This suggests that mutational footprints could potentially help identify which treatment is more suitable for a particular tumour, although this finding still requires prospective clinical validation.

The study therefore shows that the prostate cancer genome contains more than a list of mutations. It carries a record of the processes that have damaged the tumour over time. By combining different types of genomic information and relating them to clinical parameters, the researchers were able to identify patterns associated with tumour development, metastasis and treatment response. This approach could contribute to a more personalised understanding of prostate cancer and, eventually, to better treatment selection.

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