Characteristics of genomic alterations of lung adenocarcinoma in young never-smokers

Int J Cancer. 2018 Oct 1;143(7):1696-1705. doi: 10.1002/ijc.31542. Epub 2018 May 7.


Non-small-cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never-smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never-smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well-known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer-associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer-related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer-related structural variations (e.g., EML4-ALK and KIF5B-RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6-ALK) and RET (JMJD1C-RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never-smoker patients with LUAD when compared with the in-house noncancer database (p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never-smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.

Keywords: genetic predisposition; genomics; lung adenocarcinoma; next generation sequencing; young age.

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / pathology
  • Adult
  • Age Factors
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Female
  • Follow-Up Studies
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Smoking / genetics*


  • Biomarkers, Tumor