Abstract 2235: A comprehensive map of genetic interactions in childhood cancer reveals multiple underlying biological mechanisms

Despite increasing survival rates, childhood cancer is still the major cause of disease-related child death in developed countries. Genetic interactions between mutated genes play an important role in cancer development. They can be detected by searching for pairs of mutated genes that co-occur more (or less) often than expected. Co-occurrence suggests a cooperative role in cancer development, while mutual exclusivity points to synthetic lethality, a phenomenon of interest in cancer treatment research. Little is however known about genetic interactions in childhood cancer. Here, we apply a statistical pipeline to detect genetic interactions in a combined dataset comprising over 2,500 tumors from 23 cancer types. The resulting genetic interaction map of childhood cancers comprises 15 co-occurring and 27 mutually exclusive candidates. The biological mechanisms underlying most candidates are either tumor subtype, pathway epistasis or cooperation while synthetic lethality plays a much smaller role. Thus, other explanations beyond synthetic lethality should be considered when interpreting results of genetic interaction tests. Citation Format: Josephine Daub, Saman Amini, Xiaotu Ma, Natalie Jager, Jinghui Zhang, Stefan Pfister, Frank Holstege, Patrick Kemmeren. A comprehensive map of genetic interactions in childhood cancer reveals multiple underlying biological mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2235.