The landscape of genomic alterations across childhood cancers

Abstract

The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-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.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .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 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

“…This finding is in line with the link between polyploidy and the detection of rearrangements due to one-off genomic catastrophic events 10,11 . In addition, tumor cells with chromoanasynthesis showed higher total numbers of aberrations and frequently harbored marker chromosomes (Figure 2a).…”

“…At the mutational signature level, a significant association between chromothripsis and mutational signatures 3 and 8, associated with DNA repair defects, was reported in SHH medulloblastoma 11 . We confirmed the link between DNA repair deficiency and chromothripsis in additional tumor entities, namely adult glioblastoma (n=74), breast cancer (n=356) and melanoma (n=69) (Supplementary Figures 10 b-d).…”

“…Supervised mutational signature analysis of high-confidence somatic SNVs in individual samples was performed using non-negative matrix factorization formalism as described previously 11,16 . The expanded set of 30 canonical mutational signatures was used for decomposition of somatic mutations (http://cancer.sanger.ac.uk/cosmic/signatures).…”

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature

“…One study of 914 patients with childhood cancer, which was enriched for CNS tumours, considered 162 genes for investigation and reported that 7.6% (69/914) of patients with childhood cancer carried pathogenic or likely pathogenic germline variants 40. The genes with the highest number of reported germline variants included TP53 , NF1 and BRCA2 40.…”

“…One study of 914 patients with childhood cancer, which was enriched for CNS tumours, considered 162 genes for investigation and reported that 7.6% (69/914) of patients with childhood cancer carried pathogenic or likely pathogenic germline variants 40. The genes with the highest number of reported germline variants included TP53 , NF1 and BRCA2 40. The other study selected 40 childhood cancer patients with a suspected genetic predisposition to cancer, detecting pathogenic or likely pathogenic germline variants in 20% (8/40) of patients with childhood cancer 41.…”