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

Xing, Deyin; Rahmanto, Yohan Suryo; Zeppernick, Felix; Hannibal, Charlotte Gerd; Kjær, Susanne K.; Vang, Russell; Shih, Ie Ming; Wang, Tian Li

doi:10.1016/j.humpath.2017.08.021

Cited by 21 publications

(17 citation statements)

References 28 publications

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“…We found BRAF mutations in 13.8% (9/65) of LGSC, which falls within the broad range reported previously (2% -33%). 10,[13][14][15]37 This was similar to 17.9% (10/56) reported by Xing et al 37 in a similar sized cohort and slightly higher than AACR GENIE Project database, where the frequency of patients with BRAF mutations in the LGSC was 4/56 (7%, accessed April, 2017). 38 The GENIE Project contains genomic records generated in CLIA-/ISO-certified laboratories obtained at multiple tertiary referral centers 38 , and may be enriched for patients with late stage disease seeking biomarker-driven clinical trials, whereas the patients reported in the current study are prospectively recruited clinic-based cases.…”

Section: Discussionsupporting

confidence: 81%

BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

Moujaber

Etemadmoghadam

Kennedy

et al. 2018

JCO Precision Oncology

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Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

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Section: Discussionsupporting

confidence: 81%

BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

Moujaber

Etemadmoghadam

Kennedy

et al. 2018

JCO Precision Oncology

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“…More recently, NRAS mutations were described in LGSOC. Five studies identified 12 NRAS mutations (either at Q61R or Q61K) in a total of 118 cases, resulting in an average frequency of 9.3% [7], [9], [26], [27], [28]. We found three NRAS mutations in our series.…”

Section: Discussionmentioning

confidence: 46%

Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

et al. 2019

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BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian carcinoma. Limited data regarding the molecular-genetic background exist beyond mutations in the RAS signaling pathway. There is a growing need to better characterize these tumors due to chemoresistance and limited therapeutic options in advanced or recurrent disease. METHODS: We performed genome-wide copy number aberration (CNA) profiles and mutation hotspot screening ( KRAS, BRAF, NRAS, ERBB2, PIK3CA, TP53 ) in 38 LGSOC tumor samples. RESULTS: We detected mutations in the RAS-signaling pathway in 36.8% of cases, including seven KRAS , four BRAF , and three NRAS mutations. We identified two mutations in PIK3CA and one mutation in MAP3K1, EGFR , and TP53 . CNAs were detected in 86.5% of cases. None of the focal aberrations was correlated with specific clinical characteristics. The most frequently detected CNA was loss of 1p36.33 in 54.1% of cases, with a trend towards lower progression-free survival and overall survival in patients with 1p36.33 loss. CONCLUSIONS: Activating RAS mutations were dominant in our series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options. Furthermore, we detected 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker.

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“…Xing et al analyzed the NRAS mutation status of SBOTs, noninvasive LGSCs, and invasive LGSCs; interestingly, they did not find a NRAS mutation in either SBOTs or noninvasive LGSCs. According to these authors, the low prevalence of NRAS mutations implies that this gene may play a limited role in the development of LGSC [ 32 ]. However, in the study conducted by Emmanuel et al, activating NRAS mutations were found in 5 out of 58 (9%) invasive serous epithelial ovarian carcinomas coexisting with a serous borderline tumor and in none of the 53 isolated SBOTs.…”

Section: Discussionmentioning

confidence: 99%

Testing for NRAS Mutations in Serous Borderline Ovarian Tumors and Low-Grade Serous Ovarian Carcinomas

2018

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The Idylla NRAS Mutation Test, performed on the Biocartis Idylla system, is an in vitro diagnostic tool for the qualitative assessment of 18 NRAS mutations in codons 12, 13, 59, 61, 117, and 146. Low-grade serous ovarian cancer (LGSC) represents less than 10% of all serous ovarian carcinomas. LGSCs are believed to arise from preexisting cystadenomas or serous borderline tumors (SBOTs) that eventually progress to an invasive carcinoma. The molecular analysis of cancer-causing mutations and the development of targeted biological therapies constitute a milestone in the diagnosis and therapy of ovarian malignancies. According to some authors, NRAS may be an important oncogene for the progression of SBOT to a frankly invasive disease. The primary aim of this study was to verify if a fully integrated, real-time PCR-based Idylla system can be used for the rapid determination of the NRAS mutation status in patients with serous borderline ovarian tumors and low-grade serous ovarian carcinomas. The study included tissue specimens from 12 patients with histopathologically verified ovarian masses, operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz (Poland), between January 2009 and June 2012. The mean age of the study patients was 52.5 years (range 27–80 years). NRAS mutation in codon 13 (G13D, p.Gly13Asp; nucleotide: c.38G>A) was found in one patient, a woman with low-grade serous ovarian carcinoma. To the best of our knowledge, our experiment was the first published study using the novel Idylla NRAS Mutation Test for the evaluation of ovarian tumors in a clinical setting. The Idylla platform is an interesting ancillary first-line rapid and fully automated instrument to detect NRAS mutations in SBOTs and LGSCs. However, the clinical usefulness of this method still needs to be verified in larger groups of cancer patients.

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

Cited by 21 publications

References 28 publications

BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

Testing for NRAS Mutations in Serous Borderline Ovarian Tumors and Low-Grade Serous Ovarian Carcinomas

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