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Alterations of normal DNA methylation patterns have been reported in various types of human tumors. These alterations are represented by genome wide hypomethylation and by region specific hypermethylation. One commonly hypermethylated region is 17p13.3 (D17S5), the putative site of a tumor suppressor gene. In this study we report that hypermethylation at this locus occurs frequently (33%) in ovarian tumors. We reported previously that loss of chromosome 17 is a common event in serous epithelial ovarian tumors. A correlation of the methylation event and chromosome 17 loss suggests that hypermethylation at D17S5 precedes chromosome 17 loss.

Epithelial tumors of the ovary are the most common ovarian tumors of adult women. They exist in several different histological patterns and exhibit varying degrees of aggressiveness. Molecular genetic studies in epithelial ovarian cancer have shown that loss of heterozygosity (LOH) for regions of chromosome 17 is a common event, probably reflecting the inactivation of one or more tumor suppressor genes present on this chromosome. We examined 87 sporadic epithelial ovarian tumors of different grade and histological type at 16 loci on this chromosome and found that 35% of them showed LOH for chromosome 17. Of these, 84% showed LOH for all informative markers, suggesting that loss of the entire chromosome 17 homologue may have occurred. Interestingly, chromosome 17 loss was observed frequently in serous tumors (49%), was less common in endometrioid tumors (15%), and was rare in mucinous tumors (4%) (P = .01 and P = .0002, respectively). Our findings support the concept that the histological subtypes of epithelial ovarian cancer may be the result of different molecular genetic events.

Seventy-four sporadic ovarian tumors were studied for loss of heterozygosity (LOH) and microsatellite instability (MI) with 20 polymorphic markers on chromosome 17 and at least I marker on every other chromosome. Additionally, activation of the K-ras oncogene was examined through mutation analysis of codon 12. A majority of the tumors analyzed were low grade and/or of the mucinous histologic type. A negative correlation between LOH on chromosome 17 and K-ras activation was observed, with the former alteration present in the majority of high grade serous and endometrioid tumors and the latter most commonly found in the mucinous and low malignant potential (LMP) tumors. In 60% of cases where LOH on chromosome 17 was present, it was observed at all informative markers, indicating chromosome loss. In these cases, frequent events of LOH were observed on the other chromosomes. When confined events of LOH were observed on chromosome 17, fewer events of LOH were observed on the other chromosomes. In the absence of LOH on chromosome 17, LOH on other chromosomes was rare. K-ras activation was most commonly observed in tumors with no LOH events. Two endometrioid tumors and 2 mucinous tumors demonstrated MI. Our data support the involvement of different molecular pathways in the development of different types of ovarian tumors.