NRAS and BRAF Mutations in Cutaneous Melanoma and the Association with MC1R Genotype: Findings from Spanish and Austrian Populations

Abstract

There is increasing epidemiologic and molecular evidence that cutaneous melanomas arise through multiple causal pathways. To further define the pathways to melanoma, we explored the relationship between germline and somatic mutations in a series of melanomas collected from 134 Spanish and 241 Austrian patients. Tumor samples were analyzed for melanocortin-1 receptor (MC1R) variants and mutations in the BRAF and NRAS genes. Detailed clinical data were systematically collected from patients. We found that NRAS-mutant melanomas were significantly more likely from older patients and BRAF-mutant melanomas were more frequent in melanomas from the trunk. We observed a nonsignificant association between germline MC1R status and somatic BRAF mutations in melanomas from trunk sites (odds ratio (OR) 1.8 (0.8-4.1), P=0.1), whereas we observed a significant inverse association between MC1R and BRAF for melanomas of the head and neck (OR 0.3 (0.1-0.8), P=0.02). This trend was observed in both the Spanish and Austrian populations.

Endometriosis and the risk of skin cancer: a prospective cohort study

“…If these results are confirmed in future studies, this will be consistent with the “common genetic origin” hypothesis since melanomas on this location have been associated with naevus-associated gene polymorphisms (43, 44), MC1R (the red hair colour gene) status, and somatic BRAF mutations (45). …”

Melanoma Epidemiology and Prevention

“…However, studies conducted in North Carolina and Australia found no association between carriage of MC1R variants and BRAFmutant melanoma [93,228], while a study conducted in Germany found BRAFmutant melanoma to be less frequent among MC1R variant carriers than non-carriers, with the effect dependent entirely upon the nodular subtype [212]. A recent study in Spanish and Austrian populations found no association of MC1R status with BRAF-mutant melanoma across all tumor sites but a non-significant association for truncal melanoma and a significant inverse association between MC1R variants and BRAF-mutant melanomas of the head and neck [92]. Additional larger-perhaps international-studies seem necessary to provide any real understanding of the association of MC1R variants with BRAF-mutant melanoma in the context of possible anatomic site and histologic subtype dependencies.…”

“…Most studies note indirect evidence, such as associations between mutations with anatomic site, to infer a relationship to UV exposure; however, body site alone may influence mutational status. Studies examining sun exposure questionnaire data found that BRAF-mutant melanoma was associated with high early-life ambient [228] and individual self-reported childhood sun exposure [144] and was less likely to occur in people with high cumulative sun exposure [92]. However, these results remain to be replicated.…”

Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma

“…DNA was isolated using Qiagen DNeasy Tissue Kit (Qiagen) with additional proteinase K digestion at 55°C for 48 h (ref. 49).…”

“…Mutations at codon 600 of BRAF p.V600 and codon 61 of NRAS p.Q61 in DNA from FFPE samples were detected with single base extension or allele-specific assays using the iPLEX genotyping format (Sequenom) 49 . For DNA from fresh frozen tumour tissues, PCR and Sanger sequencing as described were used to detect mutations in the TERT promoter, BRAF, NRAS and additionally in CDKN2A.…”