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)

• Published in: Cancer 2019-10, Vol.125 (20), p.3535-3544
• Main Authors: Wang, Hongsheng, Ou, Qiuxiang, Li, Delan, Qin, Tao, Bao, Hua, Hou, Xue, Wang, Kaicheng, Wang, Fang, Deng, Qianqian, Liang, Jianzhong, Zheng, Wei, Wu, Xue, Wang, Xiaonan, Shao, Yang W., Mou, Yonggao, Chen, Likun
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenomatous polyposis coli; Adult; Aged; Brain; Brain cancer; brain metastasis; 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; CDK4/CCND1; CDKN2A/2B; Copy number; Correlation analysis; Cyclin D1 - genetics; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Discordance; DNA Copy Number Variations - genetics; Epidermal growth factor receptors; Female; Gene Expression Regulation, Neoplastic - genetics; Gene sequencing; Genes; genomic instability; Genomic Instability - genetics; Genomics; Health risks; Heterogeneity; High-Throughput Nucleotide Sequencing; Humans; Lung cancer; Male; Malignancy; Medical prognosis; Metastases; Metastasis; Middle Aged; Molecular modelling; Mutation; Mutation - genetics; Neoplasm Metastasis; Neoplasm Proteins - genetics; Non-small cell lung carcinoma; non–small cell lung cancer (NSCLC); Oncology; p53 Protein; PI3K pathway; prognosis; Retrospective Studies; Risk; Signal transduction; Signaling; Small cell lung carcinoma; Therapeutic applications; Thorax; Transcriptome - genetics; Wnt protein
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.32372

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. The driver mutation status is highly concordant between primary non–small cell lung cancer (NSCLC) and paired brain metastases, but increased genomic instability can be seen in brain metastases in comparison with primary NSCLC. Aberrant PI3K signaling of primary NSCLC is significantly correlated with increased brain metastasis risk.