Written by | Shen Wei, editor-in-charge, | Guo Yuelong
In recent decades, the cure rate of childhood tumors has increased to about 80%. However, in developed countries, tumors remain the leading cause of morbidity-related deaths in children over one year of age. Even if they survive, many children still have to endure long-term sequelae of surgery, chemotherapy and radiation therapy, including mental disorders, organ toxicity, and secondary tumors.
Pediatric tumors differ from adult tumors in terms of histopathology and molecular subtypes, and elucidating the complete genetic characteristics of children's tumors is important for developing more accurate and less harmful therapies.
In February 2018, a joint research team led by Professor Stefan M. Pfister of the Hope Children's Cancer Center in Heidelberg, Germany, published an article titled The landscape of genomic alterations across childhood cancers in Nature. Through a comprehensive analysis of genomic alterations in children (or adolescents/young adults) with 24 different molecular types, a number of differences significantly different from adult tumors were found in terms of mutation frequency and significant mutant genes. The main characteristics of children's tumors in terms of mutation signal, germline mutations, structural and copy number variations, and potential drug targets were analyzed, and 149 presumptive tumor genes were found. The results show:
1. There are fewer mutations and structural variations in pediatric tumor patients than in adults;
2. Childhood tumors are often driven by a single gene, and studies have shown that about 57% of tumors contain mutations driven by this single gene, and about 7.6% of tumors have been found to be related to mutations inherited from both parents;
3. Compared with adult tumors, the relevant gene mutations in children's tumors are quite different, and only about 30% of the gene mutations in the study are consistent;
4. Half of tumors contain mutations that have corresponding, existing, or targeted therapies under development.
The study integrated genome-wide and exome sequencing datasets from multiple sources to obtain a pan-cancer cohort of 961 tumor samples from 914 patients, 95 percent diagnosed at ages 18 and under, and another 5 percent 25 years and younger. Tumors of the central nervous system are the focus of this analysis.
The overall frequency of somatic mutations in childhood tumors is 14 times lower than that of adult tumors (0.13 vs 1.8 per Mb). Hypermutations (more than 10 mutations per Mb) occur only in H3.3 or H3.1 K27 wild-type high-grade gliomas with bialprole mutations in MSH6 or PMS2.
In addition, K27 wild-type high-grade glioma mutations with MSH2, MSH6, or PMS2 monoalle mutations are also more frequent. It will be of clinical significance to explore whether these highly mutant tumors respond to immune checkpoint inhibitors.
Mutation signals, which may reflect the biochemical perspective of cellular processes, have been explored in great depth in tumors. The pediatric tumor study identified 16 known mutation signals and a new signal P1, which was manifested as an increase in C>T mutations in the CCC/CCT background, mainly in some atypical malformed rhabdomyoid tumors and one case of ependymoma. Signal 16 occurs mainly in fibrous astrocytomas, and signal 18 (associated with oxidative DNA damage, C>A reversal) occurs mainly in neuroblastomas, rhabdomyosarcomas, and some other tumors with multiple structural variations. Signals 3, 8, and 13 are associated with chromosome fragmentation and TP53 mutations, particularly tube-forming neuroblastomas, adrenal cortical carcinomas, and rhabdomyosarcomas in the SHH subgroup with TP53 germline mutations. These three signals are more common in tumor types with higher genomic instability (more structural variation).
Germline mutations in tumor genetic susceptibility genes. This figure summarizes (a) the proportion of patients with one pathogenic germline mutation in each tumor type; (b) sequencing mutant genes based on the sample size involved; (c) Cellular processes associated with tumor susceptibility genes; (d) Frequency of germline mutations corrected for incidence and estimated total proportion of children's tumors that may be associated with genetic predisposition.
From the pathogenic germline mutations, this study showed that about 7.6% of children's tumors have a genetic predisposition (after correction for incidence, this proportion is 6%). The most common are adrenal cortical carcinoma (50%) and acute B lymphoblastic leukemia with subdiploidity (28%), followed by K27 wild-type high-grade gliomas, atypical malformed rhabdomyoid tumors, neuronoblastomas of the SHH subgroup, and retinoblastomas (about 15-25% each).
Germline TP53 mutations are of high clinical importance, estimated to be present in 1.5% of pediatric tumor patients and more than 10% of individual tumor types. Germline mutations are mostly related to DNA mismatch repair and double-strand break repair genes. Both groups have clinical significance, for example, patients with mismatch repair defects may be candidates for immune checkpoint inhibitors.
From a somatic perspective, the study identified 77 genes with significant mutations (SMGs), the most common category being genes associated with epimodelation, followed by transcriptional regulation and MAP kinase-related genes. Unlike germline mutations, TP53 is the only DNA repair gene among all SMGs, while 9% of adult tumors fall into this category. In addition, PI3K-related SMG is the most common in adult tumors, but only 3% of children's tumors. 47% of pediatric tumors have at least one driven SMG, of which most tumors (57%) have only one driven SMG. After correcting the incidence, the most common SMG for childhood tumors is TP53, KRAS, ATRX, NF1, and RB1.
Genes that are significantly mutated in children's tumors compared to adult tumors. The graph summarizes the 24 pediatric tumor types and the percentage of tumor samples with non-silencing mutations in 77 significantly mutated genes in this pan-cancer cohort.
The researchers also explored potential drug targets, finding 453 potential drug-targeted events (PDEs) corresponding to 59 genes. Burkitt's lymphoma and fibrous astrocytoma are more common, while not detected in ependymoma or hepatoblast carcinoma. The pathways involved include RTK/MAPK signaling, transcriptional regulation, cell cycle regulation, and DNA repair. After morbidity correction, about 52% of all primary pediatric tumors have targeted therapies that are already present or are in development. The most commonly affected are the MAPK signaling pathway and the cell cycle regulation pathway. It is particularly noteworthy that primary and recurrent tumors in the same patients often correspond to different PDEs. So when considering individualized therapy, information about the current tumor needs to be gathered.
Potential drug-targeted events in pediatric tumors. The figure summarizes (a) the proportion of primary tumors with potential drug-targeted events and the corresponding biological pathways, and (b) the proportion of patients with potential drug-targeted events after standardization based on incidence.
It is worth noting that on the same day, Nature also published a paper titled Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours completed by zhang Jinghui, a Chinese scientist at St Jude Children's Research Hospital in the United States, using similar research methods to analyze 1, Genomes, exomes, and transcriptomes of 699 pediatric leukemia and extracranial solid tumors identified driver genes in 142 of these tumors, of which only 45% were consistent with findings in similar adult cancer studies, and copy number variation and structural variation were the main events in these tumors, accounting for about 62%.
In summary, the study provides an unprecedented data resource for pediatric oncology research, and two papers open up a pan-genomics study of childhood tumors. These findings are encouraging because 7-8% of children in this cohort carry a clear susceptibility-related germline mutation, nearly 50% of children have potentially targeted genetic events for primary tumors, and many therapeutic targets are already in existence or are already in development, guiding future clinical trial design, and stratified targeted therapy will become promising.
At the same time, studies reflect the genetic predisposition of childhood tumors and require systematic consideration of genetic counseling, especially for patients with suggestive high-risk factors. In addition, the study also revealed that there is a big difference between pediatric tumors and adult tumors, and in the future, mechanism-driven drug development for children's tumors will be needed.
Writing
Editor-in-charge
make
Typography | Che Jie proofreads | uu