Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer

Oncogene. 2019 Mar;38(10):1661-1675. doi: 10.1038/s41388-018-0536-1. Epub 2018 Oct 22.

Abstract

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics
  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / classification
  • Carcinoma, Squamous Cell / genetics
  • DNA Copy Number Variations
  • Female
  • Founder Effect
  • Gene-Environment Interaction
  • Genetic Heterogeneity*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Small Cell Lung Carcinoma / genetics
  • Thoracic Neoplasms / genetics*
  • Thoracic Neoplasms / secondary*
  • Tumor Microenvironment
  • Whole Genome Sequencing / methods*