In serous ovarian neoplasms the frequency of Ki-ras mutations correlates with their malignant potential

Abstract

We analysed 44 tissue samples from serous ovarian neoplasms of different malignant potential for Ki-ras mutations by denaturing gradient gel electrophoresis (DGGE) and direct sequencing after microdissection. Point mutations at codon 12 were found in 7 of 20 tumours of low malignant potential (LMP) (35%) and in 2 of 6 well-differentiated carcinomas (33%). In contrast, no mutations were detected in the 11 poorly differentiated ovarian carcinoma samples or in the 7 serous cystadenomas. The frequency of Ki-ras mutations in serous ovarian tumours seems to correlate with the malignant potential of the neoplasms. The data favour the hypothesis of a de novo development of poorly differentiated ovarian carcinomas and do not support an evolution from LMP tumours or well-differentiated carcinomas.

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…Although a number of key molecules implicated in control of this vesicle transport chain, including DLK1 and MAP3K5, seem to be up-regulated in LMP tumors (versus highgrade invasive), the pathway has been mostly studied in the context of neuronal transport and axonal damage repair (64,65), and its relation to tumor pathobiology has not been explored. A high incidence of activating mutations in the RAS-MAPK pathway has commonly been found in LMP tumors (3,7,8,11,12), and we found either BRAF or KRAS mutations in the majority of LMP cases tested (59%, 79 of 134). We found BRAF mutations in 46% of serous LMP.…”

“…Overall, the results have suggested that LMP tumors follow a different process of cellular transformation compared with the majority of their invasive counterparts. One striking feature of LMP tumors is the high rate of KRAS and BRAF mutations, both of which are thought to act primarily through the canonical RAS-MAPK (RAS-RAF-MEK-ERK-MAP kinase) pathway (3,7,(10)(11)(12)(13). Furthermore, many serous LMP tumors have been reported to have wild-type p53 and functional p53 signaling (8,14).…”

Origins and molecular pathology of ovarian cancer

“…[38][39][40][41][42][43][44][45][46][47] It has also been demonstrated that loss of BRCA1 or BRCA2 function by a variety of mechanisms is present in the majority of both sporadic and hereditary high-grade serous and endometrioid carcinomas. 48,49 Boyd and coworkers 36 36,37 demonstrated the same mutation in the carcinoma and the adjacent normal or atypical epithelium in a small number of cases.…”

“…[38][39][40][41][42]44,45 Serous borderline tumors have a higher rate of KRAS mutations (27-36%) than high-grade serous carcinomas (0-12%). 40,46,47,[75][76][77][78] BRAF mutations, which are seen in 33-50% of serous borderline tumors of typical or micropapillary type, have not been identified in high-grade serous carcinoma. 74,76,78 A few studies analyzing and comparing serous borderline tumors and low-grade serous carcinomas have been performed only recently.…”

“…74,76,78 In contrast, BRAF mutations have not as yet been reported in high-grade conventional serous carcinoma and KRAS mutations have been reported only rarely (0-12%). 46,74,76,78 Studies utilizing other techniques have also demonstrated substantial differences between borderline tumors and/or low-grade serous carcinomas and high-grade serous carcinomas. One study has demonstrated that the allelic imbalance index gradually increases from typical to micropapillary serous borderline tumor to invasive low-grade serous carcinoma in contrast to the finding of high levels of allelic imbalance in even tiny high-grade ovarian serous carcinomas, 73 (Mok, Bell unpublished data).…”