Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

Cancers

Hui Yu¹  Scott Ness¹  Yan Guo¹  Peng Mao¹  Fei Guo²  Limin Jiang³  Jijun Tang³ 

[1] Department of Internal Medicine, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA;School of Computer Science and Engineering, Central South University, Changsha 410083, China;Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;

关键词: cancer;    mutation;    co-mutation;    prognosis;    drug sensitivity;   

DOI  :  10.3390/cancers14020415

来源: DOAJ

【 摘 要 】

Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer-sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer. Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.

【 授权许可】

Unknown