Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

Nat Commun. 2016 Jul 5:7:12072. doi: 10.1038/ncomms12072.

Abstract

Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Clone Cells
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Cytokines / genetics
  • Cytokines / immunology
  • Female
  • Genetic Heterogeneity*
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Neoplasms, Multiple Primary / genetics*
  • Neoplasms, Multiple Primary / immunology
  • Neoplasms, Multiple Primary / pathology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology

Substances

  • Cytokines
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell
  • Toll-Like Receptors