Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Cancer Cell. 2018 Dec 10;34(6):996-1011.e8. doi: 10.1016/j.ccell.2018.10.016.

Abstract

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.

Keywords: APOBEC; cancer genomics; early-onset cancer; epigenetic risk-score; mutational processes; prostate cancer; structural variants; tumor evolution; tumor evolution prediction.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • DNA Methylation*
  • Evolution, Molecular
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Risk Factors
  • Transcriptome*
  • Whole Genome Sequencing / methods

Substances

  • Biomarkers, Tumor
  • ESRP1 protein, human
  • RNA-Binding Proteins