Genetic analysis of benign ovarian tumors

Ovarian cancer represents a major cause of cancer death among women and yet remarkably little is known about its etiology. The paradigm established by the colorectal carcinogenesis model would suggest that ovarian cancers are likely to arise through malignant transformation of benign ovarian tumors. However, molecular genetic data that could answer this important question is lacking. In our study, we analyzed 80 benign ovarian tumors for TP53 and K-ras mutations and for LOH on chromosomes 6, 7, 9, 11 and 17 using 56 microsatellite markers. Twenty-five percent (5/20) of non-epithelial tumors and 73% (44/60) of epithelial tumors exhibited LOH on at least 1 chromosome arm. A particularly high frequency of LOH was detected among the epithelial tumors on chromosome arms 6q (17%), 7p (17%), 7q (27%) and 11p (18%), which are also regions of frequent LOH among ovarian carcinomas. No K-ras mutations were detected in any tumor but somatic TP53 mutations were detected in 2/34 (6%) serous and 1/26 (4%) mucinous epithelial tumors. In contrast to most previous studies our data is derived from a relatively large number of microdissected tumors and is likely to represent a more accurate picture of the frequency of alterations in these tumors. We conclude that LOH is common in benign ovarian tumors, suggesting that inactivation of tumor suppressor genes are pivotal in their development. The high frequency of alterations is consistent with their being precursors to malignant disease but does not unequivocally prove this continuum. It does however provide a framework for future analysis of the molecular genetic etiology of ovarian tumorigenesis.