Integrative clinical genomics of metastatic cancer

Nature. 2017 Aug 17;548(7667):297-303. doi: 10.1038/nature23306. Epub 2017 Aug 2.

Abstract

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

Publication types

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

MeSH terms

  • Adult
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • DNA Repair / genetics
  • Exome Sequencing
  • Female
  • Genetics, Medical*
  • Genomics*
  • Germ-Line Mutation / genetics
  • Humans
  • Male
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / pathology
  • PTEN Phosphohydrolase / genetics
  • Retinoblastoma Binding Proteins / genetics
  • Transcriptome / genetics
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human