Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations

Background: Lung adenocarcinoma (LUAD), as the most common subtype of lung cancer, is the leading cause of cancer deaths in the world. The accumulation of driver gene mutations enables cancer cells to gradually acquire growth advantage. Therefore, it is important to understand the functions and interactions of driver gene mutations in cancer progression.

Methods: We obtained gene mutation data and gene expression profile of 506 LUAD tumors from The Cancer Genome Atlas (TCGA). The subtypes of tumors with driver gene mutations were identified by consensus cluster analysis.

Results: We found 21 significantly mutually exclusive pairs consisting of 20 genes among 506 LUAD patients. Because of the increased transcriptomic heterogeneity of mutations, we identified subtypes among tumors with non-silent mutations in driver genes. There were 494 mutually exclusive pairs found among driver gene mutations within different subtypes. Furthermore, we identified functions of mutually exclusive pairs based on the hypothesis of functional redundancy of mutual exclusivity. These mutually exclusive pairs were significantly enriched in nuclear division and humoral immune response, which played crucial roles in cancer initiation and progression. We also found 79 mutually exclusive triples among subtypes of tumors with driver gene mutations, which were key roles in cell motility and cellular chemical homeostasis. In addition, two mutually exclusive triples and one mutually exclusive triple were associated with the overall survival and disease-specific survival of LUAD patients, respectively.

Conclusions: We revealed novel mutual exclusivity and generated a comprehensive functional landscape of driver gene mutations, which could offer a new perspective to understand the mechanisms of cancer development and identify potential biomarkers for LUAD therapy.