Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer

Abstract

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.

Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood

“…To elucidate whether shelterin complex mutations can predispose to the development of pediatric cancer, we analysed whole exome sequencing data of two independent parent–child cohorts of pediatric cancer patients (TRIO-D, n = 158 [ 16 ]; TRIO-DD, n = 111) for rare germline variants (minor allele frequency (MAF) < 0.2%) in the shelterin complex genes ( Supplementary Table S1 ). Overall, 23 variants were identified in 269 pediatric cancer patients ( Figure 1 B) across various tumor entities ( Figure 1 C), with missense mutations being the most prominent.…”

“…Patients ≤ 19 years of age were unselectively recruited at the Pediatric Oncology Department, Dresden (years 2019–2021), or as previously described [ 16 ]. Consent of the families was obtained according to Ethical Vote EK 181,042,019 (Dresden) and in line with the Declaration of Helsinki.…”

Risk Factors for Childhood Leukemia: Radiation and Beyond

“…The total prevalence of pathogenic germline mutations in known cancer predisposing genes in children and adolescents with leukemia is 4.4%, but this is probably only the tip of the iceberg (39). Novel techniques used for testing for hereditary cancer predisposition syndromes (CPSs), in particular whole-exome sequencing of parent-child trios, lead to the discovery of new germline risk variants (40)(41)(42). Trio sequencing can also identify new inheritance patterns in children with cancer where the family history is unremarkable and does not point to an underlying CPS.…”

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort

“…No systematic germline sequencing investigation of genetic predisposition specific to childhood ependymoma has been reported to date. Over the last decade, several large pediatric pan-cancer germline sequencing studies have been performed, with childhood ependymoma accounting for less than 5% (191/4833) of the combined sample size [ 10 – 19 ]. Taken together, these whole-exome/-genome sequencing (WES/WGS) studies report rare pathogenic germline variants in 4.7% (9/191) of children with ependymoma, although individual study estimates range from 0 to 21%.…”