Genetic Predisposition to Solid Pediatric Cancers

Abstract

Progresses over the past years have extensively improved our capacity to use genome-scale analyses-including high-density genotyping and exome and genome sequencing-to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.

Keywords: SNP; cancer predisposition genes; cancer susceptibility; genetic predisposition; germline variants; germline-somatic interaction; next generation sequencing; pediatric tumors.

Figure 1

Frequency of pediatric cancers in patients younger than 19 years. The figure shows the prevalence of the main pediatric cancer types among patients younger than 19 years of age, calculated from Centers for Disease Control and Prevention (CDC) data (United States Cancer Statistics Data, https://wonder.cdc.gov/cancer.html) and based on incidence in United States for the years 1999–2016. CNS, Central Nervous System. *This frequency is related to Wilms tumor and other non-epithelial renal tumors.

Figure 2

Global incidence of pediatric cancers in patients younger than 19 years. The graph shows the global age-specific incidence rates (ASR) per million for individual age groups (0–4 years, 5–9 years, 10–14 years, and 15–19 years) of pediatric cancer types discussed in this review. ASR reported next to the bars are calculated from International Incidence of Childhood Cancer (IICC, https://iicc.iarc.fr/) data. *These ASR include also less frequent embryonal central nervous system tumors.

Figure 3

Prevalence of germline predisposition in pediatric tumors. The percentage of germline predisposition due to uncommon, moderate-penetrance variants, reported above the bars, has been calculated evaluating the number of patients carrying pathogenic and likely pathogenic variants on the total number of patients from the cohorts analyzed for each tumor: CNS tumors: (3, 15, 17); neuroblastoma: (2, 3, 135, 146, 196, 197, 200); Wilms tumor: (3, 131, 132, 137, 148, 150, 251); osteosarcoma: (2, 3, 129, 138); rhabdomyosarcoma: (2, 3, 52, 139); Ewing sarcoma: (2, 3, 130, 146). N, number of patients analyzed in cohorts; CNS, central nervous system.