Even though the survival rate of childhood cancer has increased in the last decades to around 80% today, it is still a leading cause of death for children in developed countries. Cancer develops through the acquisition of multiple mutations, and it is assumed that genetic interactions between mutated genes play an important role in cancer onset and progression. One approach to find genetic interactions in cancer is to search for pairs of mutated genes that occur more (or less) often than expected given the frequency of the individual mutated genes. Highly co-occurring mutated genes suggest a cooperative role of these altered genes in cancer development. Mutually exclusive gene pairs can be a signal of synthetic lethality, where the combination of the two mutations is lethal for the cancer cells, and could therefore point to possible cancer treatments. We developed a statistical pipeline, based on two genetic interaction tests, to detect significant cases of co-occurrence and mutual exclusivity in two pediatric cancer data sets, comprising over 2,500 tumors from 23 cancer types. In total we detect 15 co-occurring and 26 mutually exclusive candidate genetic interactions. Nearly all candidate gene pairs are uniquely found in one cancer type, supporting earlier findings that genetic interactions are often cell or cancer type specific. Interestingly, we find that synthetic lethality is not the main cause of the mutual exclusivity patterns in our data set. The majority of these patterns can be attributed to cancer subtypes and within pathway relationships, where the effect of a mutated gene is similar to mutating a (downstream) gene in the same pathway. This initial map of genetic interactions in childhood cancer provides a solid starting point to select suitable candidates for experimental validation as well as extending the analyses to investigate the contribution of genetic interactions towards structural variants, genetic predisposition, and cellular pathways.

Citation Format: Josephine T. Daub, Saman Amini, Frank C.P. Holstege, Patrick Kemmeren. Beyond synthetic lethality: Multiple mechanisms can explain genetic interactions within childhood cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B08.