In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low‐grade serous tumours

Abstract

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

“…Mutation in other genes, including FAT3, CSND3, NF1, CDK12, RB1 and GABRA6, are also frequently identified in HGSOC tumours 15. Mutations in BRAF are restricted to serous borderline tumours, indicating that the majority of serous borderline tumours do not progress to serous carcinomas 33. Activating KRAS mutations are more common in mucinous tumours than in all other histological types 17, 34, while no mucinous tumours have been found to harbour a BRAF mutation 34.…”

Origins and molecular pathology of ovarian cancer

“…[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.…”

“…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. These studies have found a similar frequency of KRAS mutations in approximately one-third of typical or micropapillary serous borderline tumors and invasive lowgrade serous carcinomas (invasive micropapillary serous carcinoma), and BRAF mutations in an additional similar proportion.…”

“…Interestingly, KRAS and BRAF mutations are present only very rarely in the same neoplasm; thus, in aggregate these mutations are present in 60% of serous borderline ovarian tumors and 68% of low-grade serous carcinomas. 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.…”

“…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).…”