Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma

Abstract

Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of SBT to invasive low-grade serous carcinoma (LGSC) remains largely unknown. Although mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression. In this study, we analyzed NRAS exon 3 mutational status in 98 cases that were diagnosed with SBT/atypical proliferative serous tumor, noninvasive LGSC, or invasive LGSC. Of the latter, NRAS Q61R (CAA to CGA) mutations were detected in only 2 of 56 (3.6%) cases. The same mutation was not detected in any of the SBTs (atypical proliferative serous tumors) or noninvasive LGSCs. Mutational analysis for hotspots in KRAS and BRAF demonstrated a wild-type pattern of KRAS and BRAF in one of the NRAS-mutated cases. Interestingly, another LGSC case with NRAS mutation harbored a concurrent BRAF V600L mutation. These findings indicate that, although recurrent NRAS mutations are present, their low prevalence indicates that NRAS plays a limited role in the development of LGSC. Further studies to identify other oncogenic events that drive LGSC progression are warranted.

Keywords: Low-grade serous carcinoma; NRAS mutation; Oncogenic driver; Ovarian cancer; RAS signaling.

Figure 1

Representative histologic images of three different types of ovarian serous tumor. A, Serous borderline tumor/Atypical proliferative serous tumor (SBT/APST). B, Non-invasive low grade serous carcinoma (niLGSC). C. Invasive low grade serous carcinoma (iLGSC). H&E slides, Original magnification 100×.

Figure 2

Histology and nucleotide sequences of NRAS in two representative invasive low grade serous carcinoma cases. Case 1, A. H&E staining of tumor. B. Chromatogram of nucleotide sequence shows wild-type pattern of NRAS containing codon 61 in a low grade serous carcinoma. Case 2, C. H&E staining of tumor. D. Chromatogram of nucleotide sequence shows a point NRAS Q61R mutation (CAA to CGA) in a low grade serous carcinoma. H&E slides, Original magnification 40×.