NRAS mutation status is an independent prognostic factor in metastatic melanoma

Abstract

BACKGROUND: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease. RESULTS: The genotypes of the full cohort (n ¼ 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS (''WT''). Tumor mutation status was associated (P ¼ .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n ¼ 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P ¼ .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P ¼ .005; hazard ratio, 2.05). CONCLUSIONS: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma. Cancer 2012;118:4014-

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

“…[11][12][13][14][15] These results have been recently confirmed by a retrospective analysis in a large cohort of patients with advanced melanoma who underwent testing for both BRAF (exon 15) and NRAS (exons 1 and 2) mutations. 5 Finally, it is important to underline that NRASQ61R has been reported to correlate with resistance to BRAF inhibitors in preclinical and clinical data. 8,16 Because testing for NRAS mutations currently requires the use of molecular techniques that are not available in most diagnostic pathology laboratories, testing may require a dispending laborious process before NRAS testing can commence.…”

“…4 In the largest single-institution cohort of melanoma patients characterized for activating BRAF and NRAS mutations, the most common NRAS mutation was represented by the glutamine to arginine substitution at position 61 (NRASQ61R). 5 NRAS has so far proven to be intractable to conventional drug discovery, and several different strategies of directly targeting RAS have not resulted in effective therapeutics. Nevertheless, there is evidence that some NRASQ61R-mutated cell lines are sensitive to MEK inhibition in vitro.…”

Frequency and Spectrum of BRAF Mutations in a Retrospective, Single-Institution Study of 1112 Cases of Melanoma

“…A subset of this cohort was published in 2012. 10 Genomic DNA was isolated from formalin-fixed, paraffinembedded tissue sections using a PicoPure DNA extraction kit (Life Technologies, Carlsbad, CA). Microscopic glass slide tissue sections were used.…”

Emerging findings into molecular mechanism of brain metastasis

“…Numerous studies have demonstrated that about half patients with advanced melanoma have BRAF mutation, and in some studies the mutation rate even reaches as high as 60% 88. Actually, the occurrence of BRAF mutations increases the risk of BM at first diagnosis of metastatic disease 89. It is well‐known that V600E is the most common mutation in BRAF which leads to the MAPK signaling pathway aberrantly activated 90.…”