Abstract
Simple SummarySomatic 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.
Highlights
Tumors acquire somatic mutations in oncogenes and tumor suppressors that lead to tumorigenesis [1]
The most conspicuous hypermutation group existed in The Cancer Genome Atlas (TCGA)’s uterine corpus endometrial carcinoma (UCEC) cohort (Figure 1A), which seemed to be predominated by subjects having both mutated DNA mismatch repair genes and mutated POLE
The hypermutation phenomenon is closely related to several characteristics we observed for co-mutations in the UCEC cohort
Summary
Tumors acquire somatic mutations in oncogenes and tumor suppressors that lead to tumorigenesis [1]. While most studies of somatic mutations focus on the impact of single mutations, researchers have started to appreciate the cooperative effects induced by multiple mutations arising simultaneously in one tumor. Because genes are the basic genomic unit that bears a more-or-less self-contained function, researchers usually identify mutated genes and study the co-mutations between two (or multiple) distinct genes. Many studies have suggested that co-mutation is a core determinant of oncogene-driven cancers. Co-mutations have been shown to be associated with pathogenesis, immune microenvironment, therapeutic vulnerabilities of cancer, and drug sensitivity in non-small-cell lung cancer (NSCLC) [2]. Lung cancer patients with co-mutation of EGFR, TP53, and RB1 have a higher risk of histologic transformation [3]
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