Involvement of H-cadherin (CDH13) on 16q in the region of frequent deletion in ovarian cancer.

Ovarian cancer is one of the leading causes of mortality unique to women. Deletions within chromosome 6q are the most frequent events in high-grade invasive epithelial ovarian cancer (IEOC). While previous reports seem to indicate that there is loss of 16q sequences in IOEC, only a very small number of markers (single marker in two different reports) were used. In order to more precisely define the regions of deletions on 16q, we first analyzed LOH with 13 polymorphic markers on 16q in 10 benign, 3 low-grade and 21 high-grade invasive ovarian cancer samples. There was no loss with any of the markers with the benign ovarian samples and loss of one marker in one of three low-grade tumors. In contrast, 14 of 21 (67%) high-grade invasive ovarian tumors showed loss of one or more markers. Detailed deletion mapping revealed three distinct commonly deleted regions on this chromosomal arm: 10/21 (48%) of high-grade tumors showed loss at 16q23.1-23.2 (D16S518, D16S3049 and D16S3029). The second region of loss at 16q23.3-16q24.1 (D16S3144, D16S504, HSD17B2 and D16S507) was observed in 11/21 (52%) of the tumors. The highest frequency of loss was seen at 16q24.2-16q24.3 (D16S422, D16S402 and D16S520) in 12/21 (57%) of tumors. The genomic map of CDH13 indicates that the marker D16S422 that was lost in 5 of these 12 tumors is part of this gene. Three of these 5 tumors showed very low levels of CDH13 expression. Three tumors with LOH of other markers in this region also showed lower levels of CDH13 expression. Analysis of the methylation status of CDH13 in tumors with low levels of expression with methylation-specific PCR revealed that four of six (67%) tumors had methylation of one of the CDH13 alleles. These results suggest that a combination of hyper-methylation and deletion cause the inactivation of CDH13 in ovarian tumors.