Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

Simple Summary Somatic mutations are one of the most important causal factors of cancers. In this study, we show that certain mutations, when occurring simultaneously, have a stronger biological effect than their single counterpart. These effects include prognosis and drug sensitivity. 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.

Automated summary

This study highlights the importance of co-occurring mutations in cancers, which have stronger effects on prognosis, drug sensitivity, and demographic disparities compared to single mutations. Functional analysis reveals that co-mutations with higher prognostic values cause greater dysregulation of gene expression and alter RNA binding protein or micro RNA binding sequences.