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Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes
G Strathdee1, K Appleton, M Illand
1Cancer Research Campaign Department of Medical Oncology, CRC Beatson Laboratories, Glasgow University, Glasgow G61 1BD, United Kingdom.
Abstract:
Mounting evidence suggests that aberrant methylation of CpG islands is a major pathway leading to the inactivation of tumor suppressor genes and the development of cancer. Recent studies on colorectal and gastric cancer have defined a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. To determine the role of methylation in ovarian cancer, we have investigated the methylation status of 93 primary ovarian tumors at ten loci using methylation-specific polymerase chain reaction (MSP). Seven of the loci (BRCA1, HIC1, MINT25, MINT31, MLH1, p73 and hTR) were found to be methylated in a significant proportion of the ovarian tumors, and methylation of at least one of these was found in the majority (71%) of samples. Although concurrent methylation of multiple genes was commonly seen, this did not seem to be due to a single CIMP phenotype. Instead the results suggest the presence of at least three groups of tumors, two CIMP-positive groups, each susceptible to methylation of a different subset of genes, and a further group of tumors not susceptible to CpG island methylation, at least at the loci studied.
Insights
Aberrant DNA methylation is linked to cancer. In ovarian cancer, multiple genes showed methylation, but not a single CpG island methylator phenotype (CIMP), suggesting distinct tumor subgroups.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Aberrant CpG island methylation inactivates tumor suppressor genes, contributing to cancer development.
- A CpG island methylator phenotype (CIMP) is recognized in colorectal and gastric cancers, involving promoter hypermethylation of multiple genes.
Purpose of the Study:
- To investigate the role and patterns of DNA methylation in primary ovarian tumors.
- To determine if ovarian cancer exhibits a CpG island methylator phenotype (CIMP).
Main Methods:
- Methylation-specific polymerase chain reaction (MSP) was used to analyze the methylation status of ten specific gene loci.
- 93 primary ovarian tumor samples were analyzed.
Main Results:
- Seven loci (BRCA1, HIC1, MINT25, MINT31, MLH1, p73, hTR) were frequently methylated in ovarian tumors.
- Methylation of at least one locus was detected in 71% of samples.
- Concurrent methylation was observed, but results indicated at least three distinct tumor groups, not a single CIMP.
Conclusions:
- Ovarian cancers display significant DNA methylation at specific gene loci.
- The methylation patterns suggest distinct tumor subgroups rather than a uniform CIMP.
- Further research is needed to fully characterize methylation heterogeneity in ovarian cancer.