The pan-cancer analysis of gain-of-functional mutations to identify the common oncogenic signatures in multiple cancers.

Abstract Oncogenes can potentially cause uncontrolled cell growth, leading to cancer development, and these genes are normally mutated and over-expressed in tumor cells. Genomic alteration of oncogenes might result in oncogenesis and promotion of cancer progression. To date, researchers have focused mainly on the roles of oncogenes in particular cancers, but investigation of oncogenes with gain-of-function mutations in multiple cancer types are less represented in the literature. Furthermore, the effect of those gain-of-function are not validated in gene expression level. To meet this demand, we performed a systematic analysis of gene expression in oncogenes to identify the occurrence of gain-of-function mutations in pan-cancer. We identified 33,551 oncogenic mutations in 5000 samples. From our analysis, we identified three tissues with the highest frequency of gain-of-functional oncogenic mutations in hundreds of samples: breast (739 samples), central nervous system (646 samples) and large intestine (498 samples). By further counting the number of occurrences of oncogenes across cancer types, we identified a list cross-cancer mutational signatures of 99 oncogenes highly mutated in >400 samples in breast, central nervous system and large intestine samples. By further overlapping with gene expression data in the matched tumor samples, we further identified 1875 gain-of-functional mutations/events with consistent gene up-regulation in 1031 samples from multiple cancers. This result may offer additional insight into the relationship between gene dosage and oncogenesis and maybe useful in targeted cancer therapy. In summary, this study provides the first globally examining on the genetic alteration of oncogenes across cancer types. Clinical association analysis has shown that these 99 genes have a significant effect on survival. Highlights • Oncogenes with gain-of-function mutations in multiple cancer types • A systematic analysis of gene expression in oncogenes to identify the occurrence of gain-of-function mutations in pan-cancer • Gain-of-functional mutations/events with consistent gene up-regulation from multiple cancers • Additional insight into the relationship between gene dosage and oncogenesis [ABSTRACT FROM AUTHOR]