The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression

Cell. 2018 May 3;173(4):1003-1013.e15. doi: 10.1016/j.cell.2018.03.029. Epub 2018 Apr 19.

Abstract

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

Keywords: biomarkers; genomics; intra-tumoral heterogeneity; mutational signatures; prognosis; prostate cancer; subclonal reconstruction; subclonality; tumor evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood
  • High-Throughput Nucleotide Sequencing
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Polymorphism, Single Nucleotide
  • Proportional Hazards Models
  • Prospective Studies
  • Prostatic Neoplasms / classification
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Retinoblastoma Binding Proteins / genetics
  • Retinoblastoma Binding Proteins / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • NKX3-1 protein, human
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Grant support