Germline genetic landscape of pediatric central nervous system tumors

Abstract

Central nervous system (CNS) tumors are the second most common type of cancer among children. Depending on histopathology, anatomic location, and genomic factors, specific subgroups of brain tumors have some of the highest cancer-related mortality rates or result in considerable lifelong morbidity. Pediatric CNS tumors often occur in patients with genetic predisposition, at times revealing underlying cancer predisposition syndromes. Advances in next-generation sequencing (NGS) have resulted in the identification of an increasing number of cancer predisposition genes. In this review, the literature on genetic predisposition to pediatric CNS tumors is evaluated with a discussion of potential future targets for NGS and clinical implications. Furthermore, we explore potential strategies for enhancing the understanding of genetic predisposition of pediatric CNS tumors, including evaluation of non-European populations, pan-genomic approaches, and large collaborative studies.

Keywords: genetics; pediatric brain tumor; predisposition; syndromes.

Fig. 1

Distribution of tumor histology for pediatric CNS tumors, adapted from the 2017 CBTRUS statistical report. Relative distribution of pediatric CNS tumors by histology. Embryonal tumors are formed by medulloblastoma (63.6%), AT/RT (14.6%), ETMR (12.6%), and other embryonal tumors (8.9%). A license was obtained for reuse of this figure from Oxford University Press.

Fig. 2

Bar chart depicting the percentage of patients with putative pathogenic germline mutation by CNS tumor subtype. This bar chart depicts the fraction of cases affected by germline putative pathogenic mutations in cancer predisposition genes based on combining data from various studies.^,,,,, MB: medulloblastoma; RB: retinoblastoma.

Fig. 3

Age-adjusted incidence rates for various pediatric brain tumor subtypes by ethnicity (SEER data). Age-adjusted incidence rates per 100 000 with 95% CIs are depicted for PA (ICD-O-3: 9421, 9425), anaplastic astrocytoma (ICD-O-3: 9401), embryonal tumors (ICD-O-3: 8963, 9364, 9470–9474, 9480, 9490, 9500–9502, 9508), ependymal tumors (ICD-O-3: 9383, 9391, 9392, 9393, 9394), and GBM (ICD-O-3: 9440, 9441, 9442). Age-adjusted incidence rates were derived from SEER (years: 1992–2016, age: 0–19 y). AIAN: American Indian or Alaska Native, API: Asian or Pacific Islander.