KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants
Introduction
Ovarian carcinoma is the second most common type of cancer of the female genital tract in the Western World and the one with the highest lethality. Nearly 90% of cases occur sporadically, and, to date, no single causative factor has been identified. The pathogenetic mechanisms leading to this obviously heterogeneous group of ovarian tumors are largely unknown because of the lack of a universal tumor progression model.
The behaviour of borderline epithelial neoplasms is intermediate between clearly benign and obviously malignant tumors. Complex aberrations are not seen in borderline tumors, and the difference between the genetic aberrations, seen in borderline tumors and in invasive carcinomas, mainly suggest that the invasive tumors of high grade do not arise from pre-existing borderline lesions. Peritoneal implants are seen in up to 60% of borderline tumors most of serous subtype but can also be found in cases without ovarian tumors. These foci are classified by the WHO [1] as extraovarian lesions and not as metastases to reflect the indolent nature of these tumors [2], [3]. Implants are sub-classified in two subtypes, invasive and non-invasive, which often co-exist in different areas. Invasive implants behave like low-grade carcinomas. The relationship between implants, borderline tumors and invasive carcinomas of the ovary is still poorly understood.
The RAS–RAF–MEK–ERK–MAP kinase pathway is often affected in human cancer; especially RAS oncogenes play a pivotal role in tumorigenesis. RAS mutation was first described in malignant melanoma, lung and papillary thyreoid carcinoma [4], [5], [6], [7], [8], [9]. One of the three RAS-proto-oncogenes shows a mutation in 25% of all cancers; codon 12, 13 and 61 of KRAS are mostly affected [10]. KRAS mutation leads to constitutive activation of the protein by increasing GDP/GTP exchange or decreasing GTPase activity of the protein, thus leading to increased cell proliferation. Mutations of KRAS or BRAF in non-invasive and invasive carcinomas of the ovary have been previously reported [11], [12], [13], [14], [15], [16], [17], [18], [19] with KRAS mutation mostly seen in the mucinous subtype of ovarian tumors (up to 40%) and in serous borderline tumors, but not in invasive serous carcinoma. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Nearly 90% of the BRAF mutations occur within or immediately adjacent to the activation segment in exon 15, which protects the substrate binding site. In more than 90%, BRAF mutations occur as a single substitution of adenine (A) for the thymidine (T) at nucleotide position 1796, which converts a valine to a glutamic acid at position 600 (V600E) [20], [21]. BRAF mutations lead to ERK activation, and this promotes the G1/S transition of the cell cycle regulation.
BRAF and KRAS mutations are rarely both present in the same tumor, but the tumor types showing mutations of KRAS or BRAF are identical. This supports the hypothesis that KRAS and BRAF mutations are equivalent in their tumorigenic effects.
Therefore, in our study, we analysed the status of BRAF and KRAS genes in a large number of ovarian neoplasms, including carcinomas of different histological subtype, serous and mucinous borderline tumors and peritoneal implants, to validate our results with the previous findings above described.
Section snippets
Materials and methods
Paraffin-embedded material of 114 patients, including 44 serous carcinomas, 18 serous borderline tumors, 13 mucinous carcinomas, 17 mucinous borderline tumors, 13 endometrioid carcinomas, 4 clear cell carcinomas, 2 adenomas and 3 samples of normal tissue was used. All cases were retrieved from the archives of the Institute of Pathology of the Ludwig-Maximilians-University, Munich, Germany. Age of patients ranged from 19 to 87 years. All patients were treated surgically between 1984 and 2005 at
BRAF
100 cases (87.7%) could be analysed successfully for BRAF mutations both for exon 11 and exon 15. 92 cases (92%), including all serous invasive carcinomas (100%), did not show a mutation. Eight cases (8.0%), including five serous borderline tumors (31.25%), contained a mutation, each in exon 15. In all serous borderline tumors, codon 600 was affected (V600E), see Fig. 1. In the remaining three cases, the mutation was also found in exon 15, comprising one carcinoma of endometrioid type with
Discussion
In our study, we examined KRAS and BRAF mutations in ovarian neoplasms, including borderline tumors, invasive carcinomas of different subtype and peritoneal implants. Mutation of either K-RAS or BRAF is frequent in serous and mucinous borderline tumors. We could demonstrate a BRAF mutation in more than 30% of all serous borderline tumors, but only in one case of invasive mucinous carcinoma and no mutation in the group of serous carcinomas. The findings of a BRAF mutation in one carcinoma of
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