Background: Previous studies have demonstrated multiple different mutations of the same cancer genes in different subclones (multiple-hit) of the same tumors suggesting cancer gene convergence. By analyzing publically available large dataset, we sought to investigate whether multiple-hit phenomenon reflects a propensity for specific routes of tumorigenesis in certain patients with lung adenocarcinomas.

Methods: Whole exome sequencing data from the Cancer Genome Atlas (TCGA) lung adenocarcinoma study was queried and nonsilent somatic mutations (stop-gain, stop-loss, frameshift, splicing site and nonsynonymous) were analyzed. Bootstrapping was performed to investigate whether multiple-hit (≥ 2 mutations of the same gene in the same tumor) phenomenon is enriched in cancer genes (from Cancer Gene Census (CGC), Catalogue Of Somatic Mutations In Cancer (COSMIC) database excluding “Translocation only” genes) compared to all other genes (background). Using stage-stratified Cox proportional hazards regression, we examined the association between multiple-hit mutation status in well-known cancer genes and overall survival (OS) in patients who had complete staging and follow up information in the most recent TCGA survival dataset (updated on 4/10/2015). Subclonal analysis is in process to assess the clonal relationship among different mutations of the same genes in the same tumors.

Results: Somatic mutation data from 538 lung adenocarcinomas was analyzed. In total, 17,059 genes showed at least one nonsilent mutation in at least one tumor and 9,151 genes (54%) demonstrated multiple different nonsilent mutations in at least one tumor (multiple-hit). Of the 419 CGC cancer genes, 323 (77%) demonstrated multiple-hit phenomenon (p < 0.001). Totally 142,253 nonsilent mutations were identified in any genes, 27,616 (19%) of which were multi-hit mutations (background). Compared to this, 2,414 of 9,297 (26%) of nonsilent mutations identified in the 419 CGC cancer genes were multiple-hit mutations, which is significantly higher than background (26% vs 19%, p<0.001). Bootstrap resampling was performed with 10,000 samples confirmed above finding (p<0.01). Multivariate survival analyses suggested that multiple-hit mutation status was associated with worse OS for EGFR (HR 3.27, p = 0.03, in patients with stage III/IV, median OS was 0.52 vs. 3.5 years) after adjusted by stage.

Conclusions: Cancer gene convergence in lung adenocarcinomas suggests certain genes and/or pathways may be critical for carcinogenesis in certain patients. Multiple different mutations of certain cancer genes may have impact on clinical outcomes. Further studies are warranted to further investigate the clinical implications of multi-hit phenomenon and their potential role in identifying novel cancer genes.

Citation Format: Yan Xing, Jianjun Zhang, Jun Li, Jianhua Zhang, Alexandria T. Phan, Jenny C. Chang, Andrew Futreal. Multiple different mutations of same cancer genes in the same tumors from lung adenocarcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 109.