An analysis of nearly 1000 prostate tumor samples has revealed eight integrated mutational footprints (IMFs) that underpin the majority of genetic alterations found in prostate cancer genomes, some of which reflect clinical outcomes.
“We have effectively created a map of the biological processes that drive prostate cancer,” said Joachim Weischenfeldt, PhD, professor at the Biotech Research & Innovation Centre at the University of Copenhagen and Rigshospitalet, and co-lead author of the study. “It is not going to change how any man is treated tomorrow. But it runs on the kind of DNA sequencing that several health systems already carry out for cancer patients. What we are proposing is to read existing data differently, not to build a new test from scratch.”
Although prostate cancer has a high prevalence, the causes underlying the disease’s clinical heterogeneity, from indolent to highly lethal, are poorly understood, explain Weischenfeldt and co-authors in Nature. It is known that genetic mutations play a part in disease outcomes, but characterization of the full mutational process has typically investigated different classes of mutation separately.
In the current study, Weischenfeldt and team carried out a comprehensive and integrative mutational signature analysis to build a complete landscape of mutational processes in prostate cancer and study how they contribute to clinical outcomes.
The researchers used whole-genome sequencing data from 959 primary prostate cancers with diverse histopathological stages and clinical outcomes to dissect the genomic footprints caused by different mutational processes within the tumor.
Integrated analyses of multiple signature modalities, including single-base substitutions, insertion–deletions, copy number variants, and complex structural variants, revealed eight IMFs that collectively explain the mutational processes in 85% of primary prostate cancer genomes.
“These IMFs represent the key mutational processes operating in prostate cancer,” say the authors, noting that they are mainly related to hormone signaling, failures in DNA replication and repair, and to aging.
When the researchers looked into the clinical relevance of the IMFs, they found that four, present in 37% of primary tumors, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and homologous recombination deficiency.
Two different IMFs were predominant in early- and late-onset tumors, respectively, and the same IMF that was predominant in late-onset tumors predicted sensitivity to androgen receptor pathway inhibitors.
The researchers conclude that their study “delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.”
However, they caution: “While these findings are encouraging towards addressing an urgent clinical unmet need, more extensive and well-powered prospective biomarker-driven studies are warranted.”
“Our goal is to tailor treatment to each individual patient’s disease, and this brings us one step closer to making that a reality,” said Weischenfeldt.
