Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

Cancer. 2019 Oct 15;125(20):3535-3544. doi: 10.1002/cncr.32372. Epub 2019 Jul 9.


Background: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.

Methods: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.

Results: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.

Conclusions: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs.

Keywords: CDK4/CCND1; CDKN2A/2B; PI3K pathway; brain metastasis; genomic instability; non-small cell lung cancer (NSCLC); prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary
  • Brain Neoplasms / surgery
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / surgery
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Copy Number Variations / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Genomic Instability / genetics
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics*
  • Retrospective Studies
  • Transcriptome / genetics*


  • CCND1 protein, human
  • CDKN2A protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Neoplasm Proteins
  • Cyclin D1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4