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Methylation of PTCH1, the Patched-1 gene, in a panel of primary medulloblastomas
Joel I Pritchard1, James M Olson
1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Abstract:
The Sonic hedgehog (Shh) pathway is aberrantly activated in a subset of the most common malignant pediatric brain tumor, medulloblastoma (MB). Shh pathway activity is measured by expression of the target genes in the GLI family, MYCN and PTCH1, a tumor suppressor and negative regulator of the pathway. Promoter methylation of tumor suppressors is implicated in tumor formation by gene silencing. In this study, we examined whether the proximal promoter of the PTCH1 gene (variant exon 1B) is methylated in some cases of MB. The cases in which we anticipated the highest likelihood of methylation were chosen based on gene expression of indicators of Shh pathway activity. Of 21 primary MBs, four exhibited robust mRNA expression of GLI1 and MYCN as well as low or absent PTCH1 expression, suggesting Shh pathway activity in the absence of PTCH1. The methylation profile of these cases was determined by the bisulfite sequencing method and compared to the profiles of five unaffected pediatric cerebellum controls. Contrary to our hypothesis, there was no evidence of methylation in the PTCH1-1B promoter in the MB cases examined, nor was there methylation in the control cerebellum samples. Future directions include examination of distal regions of the PTCHlb promoter as well as alternative exon variants, most notably the CpG island containing PTCH1-1C promoter.
Insights
This study investigated PTCH1 promoter methylation in pediatric medulloblastoma (MB). Contrary to hypotheses, no PTCH1 promoter methylation was found in MB tumors, suggesting other mechanisms are involved in Shh pathway dysregulation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Sonic hedgehog (Shh) pathway is frequently activated in medulloblastoma (MB), a common pediatric brain tumor.
- PTCH1 acts as a tumor suppressor and negative regulator of the Shh pathway; its silencing via promoter methylation is a potential mechanism in tumorigenesis.
Purpose of the Study:
- To investigate the methylation status of the PTCH1 gene's proximal promoter (variant exon 1B) in medulloblastoma.
- To determine if PTCH1 promoter methylation contributes to Shh pathway dysregulation in MB cases with high pathway activity.
Main Methods:
- Analysis of 21 primary medulloblastoma samples and 5 pediatric cerebellum controls.
- Selection of MB cases based on high expression of Shh pathway indicators (GLI1, MYCN) and low PTCH1 expression.
- Bisulfite sequencing was used to assess methylation profiles of the PTCH1-1B promoter.
Main Results:
- No evidence of methylation was detected in the PTCH1-1B promoter in any of the examined medulloblastoma cases.
- Similarly, no methylation was observed in the PTCH1-1B promoter of control cerebellum samples.
- These findings contradict the hypothesis that PTCH1 promoter methylation silences the gene in MB.
Conclusions:
- PTCH1 promoter methylation (variant exon 1B) is not a significant mechanism for Shh pathway dysregulation in the studied medulloblastoma cohort.
- Further research should explore methylation in distal PTCH1 promoter regions and alternative exon variants, such as the PTCH1-1C promoter.
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