Pdtm-25. Genetic Susceptibility and Evolution of Pediatric Idh-mutant Infiltrating Astrocytomas
Year: 2017
Type: conference-abstract
Abstract: IDH mutations are considered rare in pediatric gliomas, especially in children under 14 years of age. Therefore, IDH-mutant pediatric gliomas have not been well characterized. Through this multi-institution study (5 institutions), we analyzed a total of 20 IDH1/2-mutant pediatric/AYA infiltrating astrocytoma specimens from 18 patients aged 4-26. The specimens include 15 low-grade (WHO grade II) and 5 high-grade (WHO grade III or IV) astrocytomas. A majority of the tumors appear to be early lesions based on the low cellularity, making them suitable for studying the order of driver mutations. Similar to their adult counterparts, nearly all pediatric IDH-mutant infiltrating astrocytomas (17 tumors, 85%) harbor TP53 mutation. In comparison, ATRX mutations are less frequent, detected in only 9 tumors (45%) including 4 low-grade (26% of all low-grade) and 5 high-grade tumors (100% of all high-grade). Six patients (30%) carry germline mutations in tumor suppressor or mismatch repair genes including TP53, MSH6, and RB1. All patients (N=3) with a germline mutation in MSH6 (a mismatch repair gene) had high-grade IDH-mutant astrocytomas with high genomic instability. In contrast, patients with germline TP53 mutation (Li-Fraumeni syndrome, LFS-N=2) had low-grade tumors with low mutation burden, morphologically and genetically similar to the sporadic cases. Notably, 7 out of 12 sporadic tumors harboring TP53 mutations had a TP53 mutant allele frequency that is greater than twice the IDH1/2 allelic frequency, after adjustment for TP53 loss of heterozygosity in 2 cases. This finding, together with the LFS-associated tumors, suggests that TP53 mutation may precede, or predispose to, IDH mutations in a significant fraction of astrocytomas in young patients. Our results not only define the molecular architecture of pediatric IDH-mutant infiltrating astrocytomas, but also provide insight into the genetic evolution of these tumors.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767597430