Comprehensive characterization of clonality of driver genes revealing their clinical relevance in colorectal cancer

Abstract

Background: Genomic studies of colorectal cancer have revealed the complex genomic heterogeneity of the tumor. The acquisition and selection of genomic alterations may be critical to understanding the initiation and progression of this disease. Methods: In this study, we have systematically characterized the clonal architecture of 97 driver genes in 536 colorectal cancer patients from TCGA. Results: A high proportion of clonal mutations in 93 driver genes were observed. 40 genes showed significant associations between their clonality and multiple clinicopathologic factors. Kaplan–Meier analysis suggested that the mutation clonality of ANK1, CASP8, SMAD2, and ARID1A had a significant impact on the CRC patients' outcomes. Multivariable analysis revealed that subclonal ANK1 mutations, clonal CASP8 mutations, and clonal SMAD2 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. The poor outcome of the subclonal ANK1 mutation may be caused by upregulation of IL4I1, IDO1, IFNG and MAPK12 which showed potential roles in tumor immune evasion through accumulation of immunosuppressive cells such as regulatory T cells and myeloid derived suppressor cells. Conclusion: These results suggested that the clonality of driver genes could act as prognostic markers and potential therapeutic targets in human colorectal cancer.