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Aberrant CpG island methylation in neurofibromas and neurofibrosarcomas
Pilar Gonzalez-Gomez1, M Josefa Bello, Dolores Arjona
1Department of C. Experimental, Laboratorio Oncogenetica Molecular, Hospital Universitario La Paz, 28046 Madrid, Spain.
Abstract:
Aberrant methylation of the promoter CpG island of human genes is an alternative gene inactivation mechanism that contributes to the carcinogenesis of human tumours. We have determined the methylation status of the CpG island of 11 tumour-related genes (RB1, p14ARF, p16INK4a, p73, TIMP-3, MGMT, DAPK, THBS1, caspase 8, TP53 and GSTP1) in 18 neurofibromas (including one plexiform neurofibroma) and three neurofibrosarcomas, as well as two non-neoplastic peripheral nerve sheath samples, using methylation-specific polymerase chain reaction. The series included sporadic and neurofibromatosis type 1-associated tumours. The incidence of aberrant methylation in the tumour samples was 52% for THBS1, 43% for MGMT, 33% for TIMP-3, 19% each for p16INK4a and p73, 14% for RB1, 5% for p14ARF, and 0% for DAPK, caspase 8, TP53 and GSTP1. No methylation of these genes was detected in the two samples of non-neoplastic peripheral nerve sheath. All but three samples in the study displayed aberrant methylation in at least one of the studied genes, and there was no correlation between methylation status and the patients' clinical parameters. These findings suggest that methylation of some tumour-related genes may play a significant role in the tumourigenesis of neurofibromas/neurofibrosarcomas.
Insights
Aberrant gene promoter methylation is frequent in neurofibromas and neurofibrosarcomas, indicating a role in tumour development. This epigenetic change was observed across multiple tumor-related genes in most patient samples.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Aberrant methylation of gene promoter CpG islands is a known mechanism for gene inactivation in human cancers.
- This epigenetic alteration contributes to the carcinogenesis of various human tumors.
Purpose of the Study:
- To investigate the methylation status of 11 key tumor-related genes in neurofibromas and neurofibrosarcomas.
- To determine if aberrant methylation plays a role in the tumorigenesis of these specific nerve sheath tumors.
Main Methods:
- Methylation-specific polymerase chain reaction (PCR) was employed to analyze the CpG island methylation status.
- The study examined 18 neurofibromas, 3 neurofibrosarcomas, and 2 non-neoplastic peripheral nerve sheath samples.
- Eleven specific tumor-related genes (RB1, p14ARF, p16INK4a, p73, TIMP-3, MGMT, DAPK, THBS1, caspase 8, TP53, and GSTP1) were assessed.
Main Results:
- Aberrant methylation was detected in 52% of THBS1, 43% of MGMT, and 33% of TIMP-3 genes.
- Other genes like p16INK4a, p73, RB1, and p14ARF showed lower methylation frequencies (19% down to 5%).
- No methylation was found in DAPK, caspase 8, TP53, and GSTP1, nor in non-neoplastic samples; however, most tumor samples showed methylation in at least one gene.
Conclusions:
- Aberrant methylation of specific tumor-related genes is a common epigenetic event in neurofibromas and neurofibrosarcomas.
- These findings suggest a significant role for gene promoter methylation in the tumorigenesis of peripheral nerve sheath tumors.
- No correlation was observed between methylation status and clinical parameters, suggesting methylation acts independently of these factors.