Genomic alterations have a profound impact on all aspects of cancer biology and therapy. Concomitant mutations involving multiple genes are intrinsically complex, and their relationship with biomarkers such as TMB and clinical outcomes such as drug response is only beginning to be explored. In this study, we systematically analyzed the impact of pairwise co-mutations of common genes on patient overall survival (OS).
We downloaded the publicly available TCGA datasets and used the LUAD lung adenocarcinoma subset for our pilot study. To limit noise, we restricted our attention to the top 48 most commonly mutated genes among LUAD patients. For each pair of genes g1 and g2 in this list, we compared the survival data of three groups of patients: those with g1 mutations only, those with g2 mutations only, and those with both g1 and g2 mutations. Kaplan-Meyer survival curves were plotted and p-values computed.
We obtained a large number of double mutants (223 out of 1128 possible pairs, ∼20%) with significantly different OS from single mutants. There was a wide spectrum of “co-mutation potential”: on one hand, genes such as AHNAK2 and ANK2 readily co-mutated with many other genes, all leading to double mutants with distinguishing OS; on the other hand, genes such as DMD or DNAH9 co-mutated with few or no other genes that led to distinguishing double mutants. In terms of OS, double mutants could be put into three broad categories: those better than either single mutant (“synthetic rescue”), those worse (“synthetic lethal”), and those in between (“averaging”). Surprisingly, many double mutants exhibited synthetic-rescue behaviors. For example, ANK2- and LRP1B-mutant patients had very similar OS, but double-mutants exhibited significantly better OS than either single mutant (p < 0.001 in each case).
In our proof-of-concept study we systematically explored the impact of co-mutations on OS. A large number of double mutants exhibited “synthetic rescue” behaviors, and we pinpointed many distinguishing gene pairs for further investigation. It remains to be seen whether co-mutations of the same pair of genes always have the same effect across cancer types, and how they interact with other bio- and clinical markers.
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Has not received any funding.
Y-A. Dong: Employee: OrigiMed. All other authors have declared no conflicts of interest.