Introduction: Glioma is the most common primary brain tumor and various genetic alterations have been identified such as TP53, PTEN, 1p/19q co-deletions, MGMT hypermethylation, EGFR, and isocitrate dehydrogenase 1 (IDH1). IDH1 mutations in gliomas, most commonly at codon 132, portend a better overall survival than those without the mutation. It is thought to be a gain-of-function oncogenic mutation but its exact mechanism in tumorigenesis has yet to be elucidated. In this study, we identified the same IDH1 mutation in gliomas resected from monozygotic twins but different TP53 mutations. The IDH1 mutation was also detected in the twins’ peripheral blood supporting the theory that it may be an early cancer predisposing genetic mutation and that another genetic alteration such as TP53 is required for gliomagensis.
Methods: DNA was extracted from frozen and paraffin-embedded tumor samples from both index patients and sequenced for IDH1 and TP53 mutations using PCR amplification and Sanger sequencing. DNA was also extracted from normal tissue near the tumor for both patients using microdissection techniques. Peripheral blood samples were collected from index patients and their parents and sequenced for IDH1 and TP53 mutations using PCR amplification and peptide nucleic acid (PNA) targeting method.
Results: Somatic R132H IDH1 mutation was identified in tumor tissue from both index patients. Different TP53 mutations were identified in tumor tissue. However, histologically normal tissue surrounding tumor was found to have the same IDH1 mutation but no TP53 mutation. R132H IDH1 mutation was detected in the blood from index patients but not from the parents. TP53 mutation was undetectable in blood from index patients and parents.
Conclusions: This example of a post-zygotic mosaic IDH1 mutation lends further support that the IDH1 mutation may be an early oncogenic predisposition event that requires a “second-hit” genetic alteration, such as TP53, for tumorigenesis.
Patient Care: developing future therapies
Learning Objectives: Learning objectives:
By the conclusion of this session, participants should be able to:
1. Discuss the oncogenic role of IDH1 mutations in gliomas,
2. Describe the utility of peptide nucleic acid targeting in detecting genetic mutations in peripheral blood,
3. Identify the importance of the “two-hit hypothesis” in gliomagenesis and potential for developing future therapeutic options.