Comparative genomic profiling of distant metastatic and nondistant metastatic lung adenocarcinoma

Author:Gang Chen, Beibei Mao, Jianing Yu, Hao Guo, Wanning Yang, Henghui Zhang, Zhiming Chen

Background: The majority of deaths from lung cancer are due to distant disseminated disease rather than the primary tumor. Understanding of the biology behind distant metastasis (DM) is helpful for the effective prediction of it and is crucial for reduction of the recurrence rate.  Comprehensive genome analysis of the tumor provides a new strategy for uncovering the pathogenesis and molecular diagnosis of distant metastasis in lung adenocarcinoma. 

Methods: 22 eligible lung adenocarcinoma patients (pts) were enrolled in this study. DNA was extracted from FFPE samples of the primary tumors from 8 pts with distant metastasis (DM) and 14 pts without distant metastasis (non-DM). Comprehensive genomic profiling was performed using a 1.15M size panel covering exon regions of 1,086 genes based on next generation sequencing assay. Tumor gene alterations were analyzed to investigate the difference of molecular features between the lung adenocarcinoma with or without distant metastasis.

Result: The most frequently mutated genes were TP53 (73%). Mutations of EGFR were more common in DM pts (7/8 in DM, 6/14 in non-DM). The most frequently amplified gene was RICTOR (55%). Amplification was also detected for other genes such as RAC1 (36%), EGFR (36%), FDPS (32%), CCND1 (18%), HRAS (14%), RNF43 (14%). Interestingly, the amplification of RNA43 and HRAS were only identified in DM pts rather than non-DM pts (p<0.05). In addition, copy number variation of RICTOR, RAC1 and CDKN2B occurred more often in DM pts (p<0.05). 

Conclusion: Comprehensive genomic profiling of lung adenocarcinoma reveals distinctive genomic alterations between DM pts and non-DM pts. Several possible candidate genes that may be helpful for distant metastasis of lung adenocarcinoma were identified in this small cohort. The molecular features of the primary tumor may be used as predictors of distant metastasis in lung adenocarcinoma. Expanded prospective cohorts are warranted to further elucidate these findings.