The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer

Cell Rep. 2019 May 28;27(9):2690-2708.e10. doi: 10.1016/j.celrep.2019.04.098.

Abstract

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.

Keywords: TCR repertoire; breast cancer; clade mutations; genomic landscapes; immune landscapes; immunoediting; metastases; metastatic phylogenies; private mutations; stem mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / secondary
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genomics / methods*
  • Humans
  • Loss of Heterozygosity
  • Mutation*
  • Neoplasm Metastasis
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Whole Exome Sequencing

Substances

  • Biomarkers, Tumor