Somatic evolution of prostate cancer: mutation, selection, and epistasis across disease stages
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Background
Somatic mutations involved in prostate cancer tumorigenesis and disease progression have been identified, but their evolutionary dynamics—including differential selective pressures across oncogenesis and metastatic spread—remain poorly understood. No prior study has systematically quantified the adaptive landscape from prostate organogenesis through tumor initiation and progression to metastatic castrate-resistant prostate cancer (mCRPC), nor characterized the selective epistatic interactions that structure this evolutionary trajectory.
Methods and Findings
To address this gap, we analyzed 2,704 low- and high-risk primary tumors and metastatic castration-resistant prostate cancers to quantify the mutation rates, mutational processes, and scaled selection coefficients of somatic mutations across disease stages. Trinucleotide mutational patterns were stable, but both mutation load and mutation rates increased with progression. In parallel, selective pressures on specific somatic mutations changed substantially, revealing a dynamic adaptive landscape. Stage-specific selective effects were associated with significant synergistic and antagonistic selective epistasis among key driver genes. Early selection on SPOP mutations in the BRD3 binding domain were under strong positive selection, and they increased selection for subsequent RHOA mutations while decreasing selection for TP53 mutations. Antagonistic selective epistasis was evident between mutations of CUL3 and both SPOP and PIK3CA . Mutations in KMT2C increased the selection for mutations in TP53 , consistent with their frequent co-occurrence. Synergistic epistatic interactions between mutations of PTEN and both PIK3CA and AR support a strong therapeutic rationale for combined inhibition of PI3K/AR pathway in PTEN-deficient prostate cancers.
Conclusions
These findings provide a comprehensive map of the evolving selective and epistatic forces that shape prostate cancer progression across clinical stages. By distinguishing shifts in selection from changes in mutation rate and revealing the extents of cooperative and conflicting relationships among driver mutations, our work identifies critical points of vulnerability and informs that design of therapeutic strategies that anticipate and intercept the somatic evolutionary trajectory of prostate cancer.
