Abstract
The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.
Highlights
The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer
We employed a statistical test based on log-linear regression - a generalization of the chi-square test to more than two dimensions—to identify interactions between somatic mutations and copy number alterations (CNAs) in 201 cancer driver genes across ~10,000 tumors representing 33 types of cancer characterized as part of the TCGA project[21,22,23]
Interactions were detected for 26 TSGs (65.0% of the detected genes), 12 OGs (30.0 %) with a total of 63 interactions between mutations and CNA loss, and 24 interactions between mutations and CNA gain (8 interactions were detected in both the loss and gain models; FDR = 10%, Fig. 1c; the results for all tested pairs are shown in Supplementary Fig. 3 and Supplementary Data 1)
Summary
The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. Large-scale cancer genome sequencing presents an opportunity to systematically investigate the dosage sensitivity of OGs and the dominance of TSGs and the extent to which these are fixed or variable In model organisms such as yeast, the activity-fitness functions of genes have been systematically experimentally quantified. Using data from ~10,000 tumors we show here that both OGs and TSGs quite often vary in whether they behave as one-hit or two-hit drivers These changes in dosage sensitivity and dominance are examples of the interactions between mutations being contingent upon the context. Our results suggest that the second hit in one driver and a hit in another driver in the same biological pathway can sometimes have similar consequences and be alternative evolutionary paths to cancer
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