Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cancer Genetics

Background:

• The Hedgehog (Hh) pathway is implicated in adult glioma growth.
• Isocitrate dehydrogenase (IDH) mutations are common in WHO grades II and III gliomas and secondary glioblastomas.
• Hh pathway activation in lower-grade gliomas suggests potential involvement in their progression to glioblastoma.

Purpose of the Study:

• To investigate the operational status of the Hh pathway in adult gliomas.
• To define molecular and histopathological glioma subtypes that are responsive to Hh pathway signaling.
• To correlate Hh pathway activity with IDH mutation status and glioma grade.

Main Methods:

• Sequencing of IDH genes in adult glioma specimens.
• Assaying for an operational Hh pathway using molecular markers like PTCH1.
• Measuring Hh pathway indices in primary glioma cultures and xenografts.
• Analyzing glioma specimens across different WHO grades (II, III, and IV).

Main Results:

• A correlation was observed between IDH mutations and elevated PTCH1 levels (an Hh target) in grades II-IV gliomas.
• The Hh pathway was operational in IDH-mutant gliomas, including glioblastomas derived from lower-grade lesions.
• The Hh pathway was not operational in IDH-wildtype glioblastomas without a history of lower-grade disease.
• Hh pathway modulation was also detected in some grade III gliomas with wild-type IDH.
• The Hh pathway is operational in gliomas showing evidence of progression from lower-grade tumors.

Conclusions:

• The Hedgehog (Hh) pathway is active in a subset of adult gliomas, particularly those with IDH mutations and those progressing from lower-grade tumors.
• Defining Hh-responsive glioma subtypes can improve the clinical monitoring and targeting of this pathway.
• Gliomas with this specific molecular progression route may originate from Hh-responsive cell types.