Abstract
BackgroundCancer genes tend to be highly mutated under positive selection. Better understanding the recurrently mutated genes (RMGs) in cancer is critical for explicating the mechanisms of tumorigenesis and providing vital clues for therapy. Although some studies have investigated functional impacts of RMGs in specific cancer types, a comprehensive analysis of RMGs and their mutational impacts across cancers is still needed.MethodsWe obtained data from The Cancer Genome Atlas (TCGA) and calculated mutation rate of each gene in 31 cancer types. Functional analysis was performed to identify the important signaling pathways and enriched protein types of RMGs. In order to evaluate functional impacts of RMGs, differential expression, survival, and pairwise mutation patterns analyses were performed.ResultsTotally, we identified 897 RMGs and 624 of them were specifically mutant in only a single cancer type. Functional analysis demonstrated that these RMGs were enriched in hydrolases, cytoskeletal protein, and pathways like MAPK, cell cycle, PI3K‐Akt, ECM receptor interaction, and energy metabolism. The differentially expressed genes potentially affected by the same common RMG showed a relatively low overlap across different cancer types. For the 19 Mucin (MUC) family genes, nine of them were RMGs and four of them (MUC17, MUC5B, MUC4, and MUC16) were common RMGs shared in 8 to 17 cancer types. The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis. Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated. In addition, pairwise mutation pattern analysis revealed the high frequency of co‐occurred mutations among RMGs in STAD.ConclusionThrough the functional analysis of RMGs, we found that six signaling pathways were disrupted in most cancer types and that energy metabolism was abnormal in tumors. The results also revealed a strong correlation between recurrently mutated genes from MUC family and human survival. In addition, gene expression and survival prognosis were associated with different mutation types of RMGs.
Highlights
DNA mutation is a driver event in cancers
To analyze the functional effects of mutations, we identified differentially expressed genes (DEGs) potentially affected by each common RMGs (cRMGs), whereas these DEGs showed a relatively low overlap across different cancer types, except for the DEGs affected by TP53 mutations
The results showed that six cRMGs including OBSCN, CDKN2A, CSMD3, DMD, DNAH5, and KMT2Cwith MS or NS mutations have significant associations with prognosis in several cancer types (Figure 5c)
Summary
DNA mutation is a driver event in cancers. The accumulation of necessary somatic mutations is a leading cause of cancer initiation and development (Vogelstein & Kinzler, 1993). Dozens of significantly mutated genes in various canonical signaling pathways were identified in Muscle‐Invasive Bladder Cancer (BLCA), which highlighted the importance of these pathways in the disease (Robertson et al, 2017). These findings reveal diverse functions of RMGs in cancers. Some studies have identified the RMGs and investigated their roles in a specific cancer type, a systematic analysis of RMGs and the mutation impacts on gene expression and prognosis across cancers is still needed. This work systematically investigated RMGs and their functions through pan‐cancer analysis, which provided clues to reveal the mechanisms of carcinogenesis and identify therapy targets
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