k-ras Mutation May Be an Early Event in Mucinous Ovarian Tumorigenesis

Abstract

We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear "transition" zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.

Whole-Genome Allelotyping Identified Distinct Loss-of-Heterozygosity Patterns in Mucinous Ovarian and Appendiceal Carcinomas

“…They also found 23% LOH rate in 6q27, which was significantly lower than 53% identified in serous cancer (22). High K-RAS mutation rates were also found in mucinous borderline and invasive ovarian carcinomas (23,24). Ikeda et al (25) and Wertheim et al (26) identified one of seven and two of five mucinous ovarian carcinomas, respectively, with TP53 mutation.…”

Origins and molecular pathology of ovarian cancer

“…Most studies have shown a high and increasing frequency of KRAS mutations in mucinous cystadenomas, borderline tumors and carcinomas, ranging from 33 to 86%. 47,70,72,75,87,88 Several groups 75,87,88 have noted similar KRAS mutation patterns in benign, borderline and malignant mucinous areas within the same neoplasm, which suggests that KRAS mutation is an early event in mucinous tumorigenesis. It has also been noted that the rate of TP53 mutations is lower in mucinous borderline tumors than mucinous carcinomas (13 vs 40%).…”

Expression Profiling of Mucinous Tumors of the Ovary Identifies Genes of Clinicopathologic Importance

“…Further studies have shown similar molecular alterations in all mucinous ovarian tumor types. For example, identical K-ras mutations are frequently found in coexisting borderline and invasive epithelia within a mucinous tumor (16). More importantly, these mutations are not related to the stage of the disease in mucinous tumors, unlike nonmucinous tumors, suggesting a continuum in the development of this cancer (17)(18)(19)(20).…”