Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas

Abstract

Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.

Keywords: brain tumors; cancer predisposition; genetics of cancer; high grade gliomas; pediatric neuro- oncology.

Figure 1

Molecular pathways of Li-Fraumeni (LFS) Syndrome. The two known mutation for LFS are represented here (P53 and CHK2) as lighting bolt. A group of protein kinases such as ATM, ATR, CHK1, CHK2 is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein ARF. In a normal cell, p53 is inactivated by its negative regulator, MDM2. Upon oncogene activation, various pathways will lead to the dissociation of the P53 and MDM2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. Adapted from “P53 Regulation and Signaling,” by BioRender.com (2020). Available online at: https://app.biorender.com/biorender-templates.

Figure 2

Molecular pathways of Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). MSH2 dimerizes with MSH6 to form the MutSα complex, which is involved in base mismatch repair and short insertion/deletion loops. The formation of the MSH2-MSH6 heterodimer accommodates a second heterodimer of MLH1 and PMS2. This protein complex formed between the 2 sets of heterodimers enables initiation of repair of the mismatch defect by recruiting PCN/EXO1/RCF. RFC is essential for PCNA loading and function in DNA replication. PCNA loads onto double-strand breaks and promotes Exo1 damage association through direct interaction with Exo1. By tethering Exo1 to the DNA substrate, PCNA confers processivity to Exo1 in resection. This role of PCNA in DNA resection is analogous to its function in DNA replication where PCNA serves as a processivity co-factor for DNA polymerases such as polymerases δ. DNA Pol δ is an enzyme used for both leading and lagging strand synthesis by engaging Ligase I and IV. Adapted from “DNA Repair Mechanisms by BioRender.com (2020). Available online at: https://app.biorender.com/biorender-templates.