Genetic analysis of benign ovarian tumors

Abstract

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 nonepithelial 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.

Copy Number Aberrations in Benign Serous Ovarian Tumors: A Case for Reclassification?

“…The absence of detectable KRAS, BRAF, ERBB2, or TP53 mutations in the epithelial component of any benign serous lesion in this study is consistent with the low rate of such mutations reported from previous studies (17,31). Reports of KRAS and BRAF mutations in ovarian serous cystadenomas and cystadenofibromas have been limited to a small number of cases with a coexisting region of atypical proliferation or adjacent SBT (14).…”

“…Where CN/LOH aberrations were observed in the epithelial components these were similar to those identified in previous studies of benign serous tumors (Table 3; ref. 30,31). Although the rate of epithelial CN/ LOH events in this study is significantly lower than previously reported, artifactual LOH events may have been introduced when conducting microsatellite analyses on low quantities of DNA in these previous studies (32).…”

Chromosome 3 Anomalies Investigated by Genome Wide SNP Analysis of Benign, Low Malignant Potential and Low Grade Ovarian Serous Tumours

“…LOH analyses of 3p loci are consistent with SNP analyses suggesting that 3p anomalies are rare occurrences in benign serous tumours, as are anomalies associated with other chromosomes. Although independent LOH analyses have shown low frequencies of loss of chromosomes 6, 7, 9 and 10, only a limited number of loci were examined [43], [44]. Array CGH studies have identified both gains and losses of chr6, and losses of 1p, 4q and 5q [7], [28].…”

Pre-Invasive Ovarian Mucinous Tumors Are Characterized by CDKN2A and RAS Pathway Aberrations

“…In contrast to serous cystadenomas and cystadenofibromas in which such mutations are not observed (27)(28)(29), the rate of KRAS mutation in mucinous cystadenomas has been reported at 46% to 55% (30)(31)(32). This rate increases to 63% to 73% in borderline tumors (31,33) and 75% to 85% in mucinous carcinomas (31,33).…”