A systematic analysis of genetic interactions and their underlying biology in childhood cancer

Josephine T Daub,Jinghui Zhang,Denise J E Kersjes,Frank C P Holstege,Natalie Jäger,Xiaotu Ma,Patrick Kemmeren,Saman Amini,Stefan M Pfister

doi:10.1038/s42003-021-02647-4

Abstract

Childhood cancer is a major cause of 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 known about genetic interactions in childhood cancer. 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 explanation of most candidates points to 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 genetic interaction test results.

Highlights

Childhood cancer is a major cause of child death in developed countries
Considering the extensive literature search performed for all candidate genetic interactions from both data sets (Table 2, Supplementary Note 1), we found that cancer subtype (12 gene pairs) is the most likely underlying cause in about 44% of the mutually exclusive candidates and 29% of all candidates
Most of the candidate gene pairs were detected with both tests, confirming that the faster WeSME test is a good alternative for the permutation test

Summary

Introduction

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. The resulting genetic interaction map of childhood cancers comprises 15 cooccurring and 27 mutually exclusive candidates. While adult cancers usually occur late in life as the result of a gradual accumulation of somatic mutations, pediatric cancers are rather thought of as developmental diseases. They usually have a different cell of origin compared to adult tumors[4]. Larger numbers of sequenced tumors for pediatric cancers are available, allowing the identification of genes that are frequently mutated across cancer genomes[6,7]

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Conclusion