Elsevier

Gynecologic Oncology

Volume 103, Issue 3, December 2006, Pages 883-887
Gynecologic Oncology

KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants

https://doi.org/10.1016/j.ygyno.2006.05.029Get rights and content

Abstract

Objective.

Mutations of BRAF, a downstream mediator of K-RAS, have been described in serous borderline tumors of the ovary. Data concerning other types of ovarian tumors are scarce. Therefore, we assessed KRAS and BRAF mutation in a series of more than 100 different ovarian tumors.

Methods.

Paraffin-embedded material, including invasive carcinomas, borderline tumors, benign lesions and implants, was used. BRAF codon 600 in exon 15 and K-RAS codon 12 in exon 2 were analysed.

Results.

92 cases (92%), including all serous carcinomas (100%), did not show a mutation of BRAF. Eight cases (8.0%), including five serous borderline tumors (31.25%), contained a mutation. In all serous borderline tumors, codon 600 was affected. The remaining three cases were invasive carcinomas of endometrioid (mutation on codon 600), mucinous (mutation on codon 600) and clear cell (mutation on codon 615) subtype. There was no BRAF mutation in mucinous borderline tumors. Regarding K-RAS, 89 cases (87.25%) did not show an aberration. The 11 positive borderline tumors (10.7%) were of serous (22.2%) and of mucinous type (46.6%). There was a KRAS mutation in a serous and a mucinous invasive carcinoma each. BRAF and K-RAS mutations were mutually exclusive and not seen in implants.

Conclusion.

Mutation of either K-RAS or BRAF is frequent in borderline tumors but is not found in invasive serous carcinomas and is very rare in other invasive subtypes. This supports the notion of different pathological pathways. For the development of extraovarian implants, further studies are observed.

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

References (29)

  • K. Naoki et al.

    Missense mutations of the BRAF gene in human lung adenocarcinoma

    Cancer Res

    (2002)
  • E.T. Kimura et al.

    High prevalence of BRAF mutation in thyreoid cancer

    Cancer Res

    (2003)
  • M.L. Gemignai et al.

    Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma

    Gynecol Oncol

    (2003)
  • G. Singer et al.

    Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinomas

    J Natl Cancer Inst

    (2003)
  • Cited by (0)

    View full text