Abstract
Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
Highlights
Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology
We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA)[7]
Some alteration types and rarer entities are still under-represented and significance analyses are probably limited, this dataset of nearly 1,000 tumours provides an unprecedented data resource for paediatric cancer research, further complemented by the accompanying pan-c ancer study[9]
Summary
Together with genes directly affected by breakpoints, in total 70 structural variant-r elated putative cancer genes were found, many associated with cell cycle or growth (for example, the tumour suppressor PTPRD) or epigenetic regulators (such as SUZ12)[42,43] (Extended Data Fig. 8c, Supplementary Tables 18, 19). The analysed genomic alterations were combined into 166 ‘likely functional events’ (LFEs) affecting 149 genes, classified as M-(mutation)-type or as SC-(structural/copy-number variant)-type (Extended Data Fig. 10a, Supplementary Table 20). Drug targets in childhood cancers To assess the status of druggability of childhood cancers, the cohort (n = 675 with full genomic information; WES-only, n = 39; see Methods) was screened for potentially druggable events[19] (PDEs, that is, alterations in 179 genes with a directly or indirectly targeted treatment currently available or under development; Supplementary Table 22). TERT BRAF MYC 8q24.22 12q24.31 OTX2 15q25.3 17p11.2 17q25.1 SETBP1 CCNE1 C19MC/ TTYH1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
