Comparative molecular profiling of distant metastatic and non-distant metastatic lung adenocarcinoma

Zhiming Chen, Gang Chen, Zhongqi Wang, Jianing Yu, Henghui Zhang, Beibei Mao,  Haitao Ma

Abstract:

Most lung cancer deaths are caused by a distant disseminated disease rather than primary tumors. Understanding the biology behind distant metastasis (DM) is crucial for the effective prediction and reduction of recurrence rates. Genome-wide analysis of the tumor provides a new way to explore the pathogenesis and molecular diagnosis of metastasis in lung adenocarcinoma. In our study, a total of 215 eligible lung adenocarcinoma patients were enrolled. The DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples from the primary tumors of these patients. Comprehensive molecular profiling was performed using a panel covering the exome of lung cancer-associated driver genes based on targeted next-generation sequencing. Tumor gene alterations were analyzed to investigate the differences in molecular features between lung adenocarcinomas with or without DM. Patients with DM of lung adenocarcinoma had significantly more variations in overall copy number (defined as Copy Number Alteration (CNA) load and Copy Number Instability (CNI) score). Interestingly, the study of the relationship between copy number variation and other molecular features verified that the degree of copy number variation has a positive correlation with mutations of DNA damage repair pathway (DDR). Thus, the additional analysis further revealed that metastatic patients accumulated more mutations in the DDR pathway, suggesting that impaired function of the DDR pathway and copy number variations play important roles in the invasion process of cancer cells. A comprehensive genetic analysis of lung adenocarcinoma revealed significant genomic changes between DM and non-DM patients. This finding may shed new light on the elucidation of lung cancer invasion mechanisms, and provide potential predictors for metastatic lung cancer.