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Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma.

ABSTRACT: Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis.

SUBMITTER: Thomas NE

PROVIDER: S-EPMC5701875 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma.

Thomas Nancy E NE Edmiston Sharon N SN Kanetsky Peter A PA Busam Klaus J KJ Kricker Anne A Armstrong Bruce K BK Cust Anne E AE Anton-Culver Hoda H Gruber Stephen B SB Luo Li L Orlow Irene I Reiner Anne S AS Gallagher Richard P RP Zanetti Roberto R Rosso Stefano S Sacchetto Lidia L Dwyer Terence T Parrish Eloise A EA Hao Honglin H Gibbs David C DC Frank Jill S JS Ollila David W DW Begg Colin B CB Berwick Marianne M Conway Kathleen K

The Journal of investigative dermatology 20170824 12

Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF<sup>+</sup> were associated with younger age, blond/light brown hair, increased nevi ...[more]

PMID: 28842324

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Project description:BackgroundHotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear.MethodsThe mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed.ResultsMutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p?<?0.001) and truncal localization of the culprit primary (p?=?0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p?=?0.013) and development of metastatic disease (p?=?0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p?=?0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02?-?3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15?-?6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors.ConclusionsNRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.

Dataset Information

Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma.

Publications

Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma.

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