Primary Ovarian Carcinomas Display Multiple Methylator Phenotypes Involving Known Tumor Suppressor Genes

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 methylationspecific 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. In human genomic DNA the CpG dinucleotide is generally underrepresented and the majority exhibit methylation at the 5Ј position of the cytosine.

Differential Methylation Profile of Ovarian Cancer in Tissues and Plasma

“…For the remaining two genes, methylation of HIC1 was identified in ovarian tumors, 19 but PAX5 involvement was not reported previously. Our results correlated well with data from the Cairns' group, who described increased methylation of BRCA1 and RASSF1A in serum of ovarian cancer patients 20 ; while RASSF1A was among the genes tested, it was not selected as an informative gene in our analysis.…”

“…Complete or partial inactivation of several of these genes is well-established for ovarian cancer: BRCA1 is either mutated 22 or its promoter is methylated 23 ; loss heterozygosity (LOH) is frequent at the 22q13 locus that contains EP300; 24 a combination of LOH and methylation is found for DNAJC15 (MCJ) 25 and MLH1; 21 frequent methylation is observed in promoters of TP73 19 and PYCARD (TMS1). 26 For other genes (CDKN1C-p57, PGR, and The accuracy of the biomarker for cancer detection has been established by stratified cross-validation as described in the Materials and Methods.…”

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

“…Furthermore, some types of cancer demonstrate a characteristic 'methylator phenotype' in which multiple genes (mostly MINTs, methylated in tumors) are concurrently methylated. [11][12][13] It is not clear yet as to what causes these different patterns of methylation, but it is likely that some selective growth advantages are gained during transformation. It has been well documented that silencing of tumorsuppressor genes by promoter hypermethylation contributes to the transformation process.…”

“…Recent reports demonstrate significant methylation in adult ALL and stability in relapsed tumors. 23,24 However, no specific methylator phenotype as described in solid tumors [11][12][13] has been reported in hematological malignancies. A correlation with prognosis has been suggested for individual genes such as p21 25 and O 6 MGMT.…”

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

“…DNA methylation may serve as a marker for the differential diagnosis of cancer and as a means of assessing the prognosis of cancer patients 18, 19, 20, 21. Aberrant DNA methylation is a common epigenetic event leading to the inactivation of tumor suppressor genes in ovarian cancer 22, 23. In addition, hypermethylation of many genomic regions associated with transcriptional silencing has also been shown in different histological subtypes of ovarian cancer 24, 25.…”