Genomic mapping of metastatic organotropism in lung adenocarcinoma

Cancer Cell. 2023 May 8;41(5):970-985.e3. doi: 10.1016/j.ccell.2023.03.018. Epub 2023 Apr 20.


We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.

Publication types

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

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • DNA Copy Number Variations
  • DNA Helicases / genetics
  • Genomics
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Mutation
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics


  • SMARCA4 protein, human
  • DNA Helicases
  • Nuclear Proteins
  • Transcription Factors