RT Journal Article
SR Electronic
T1 Phenotypic associations of consensus driver genes in hepatocellular carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 166090
DO 10.1101/166090
A1 Kumardeep Chaudhary
A1 Liangqun Lu
A1 Olivier B Poirion
A1 Travers Ching
A1 Lana X Garmire
YR 2017
UL http://biorxiv.org/content/early/2017/07/20/166090.abstract
AB Background Hepatocellular carcinoma (HCC) is the main form of malignant liver cancer with poor survival. Although some critical driver aberrations were identified in HCC, neither the transcriptomic nor the clinical associations of many of these driver genes have been well-characterized.Methods We used MutSigCV and OncodriveFM to identify the consensus driver genes across six HCC cohorts with significant functional impacts. We performed mutual exclusivity analysis among these drivers, as well as survival and association analyses between these drivers and physiological/clinical factors. We used generalized linear regression model to assess the impact of driver genes on transcriptome.Results Using six international HCC cohorts comprising 1,494 samples in total, we obtained a consensus of 11 driver genes including TP53, CTNNB1, ALB, AXIN1, RB1, ARID1A, RPS6KA3, ACVR2A, NFE2L2, CDKN2A and HNF1A. We found that some of these driver genes are significantly associated with gender (TP53, CTNNB1, ALB), grade (TP53, ALB, RB1) and age (CTNNB1, AXIN1, RB1) in multiple cohorts. Moreover, these driver genes are significantly associated with patients’ overall survival. Integrative analysis of driver mutations, copy number variations and transcriptomic data reveals that these driver genes are associated with the majority (63%) of the mRNA transcriptome, but only a small fraction (9%) of miRNAs. Genes associated with TP53, CTNNB1, ARID1A and HNF1A mutations contribute to four most densely connected clusters of biological pathways.Conclusions In summary, this study reveals the vast impacts of driver gene mutations (genotype) in HCC phenotypes. The consensus drivers may be valuable therapeutic targets of HCC.