The influence of melanocortin-1 receptor gene polymorphisms on the clinical-biological tumor profile and prognosis in patients with cutaneous melanoma

Introduction. The melanocortin-1 receptor (MC1R) gene is one of the key factors in susceptibility to cutaneous melanoma (CM). The influence of specific germline MC1R polymorphisms on disease aggressiveness, tumor morphology, and patient survival has not been sufficiently studied.

Objective: to comprehensively assess the associations of five key polymorphic variants of the MC1R gene (R151C, R160W, D294H, R163Q, I155T) with constitutional characteristics, primary tumor parameters, overall survival (OS), and event-free survival (EFS) in patients with CM.

Material and Methods. A single-center retrospective cohort study included 213 patients with primary CM at stages I–III. Genotyping was performed using allele-specific real-time PCR with melting curve analysis. The χ² test, Fisher’s exact test, and Mann-Whitney U test were used. Survival analysis was conducted using the Kaplan-Meier method with the log-rank test; multivariate Cox regression was applied to identify independent prognostic factors.

Results. Specific phenotypic profiles were established: R151C was associated with male sex, skin phototype I–II, and a history of severe sunburns (p<0.05); R160W was associated with the “red hair/ freckles” phenotype (p<0.05). Carriers of R151C had tumors with greater thickness (p<0.001). The most significant differences were found in prognosis: carriers of the D294H and I155T alleles demonstrated the lowest survival rates. The five-year OS for D294H was 28.4 % compared to 66.7 % in the wild-type group (p<0.001). In the adjusted model, only D294H (HR=4.21; 95 % CI 1.92–8.97; p<0.001) and I155T (HR=3.72; 95 % CI 1.65–8.39; p=0.001) remained independent predictors of unfavorable OS. The influence of R151C on the outcome was mediated by unfavorable morphological features.

Conclusion. The contribution of MC1R polymorphisms to the course of CM is heterogeneous. The D294H and I155T alleles are independent determinants of an extremely unfavorable prognosis, while R151C serves as a marker of a high-risk phenotype and a locally aggressive tumor, and R160W determines only a constitutional phenotype. The data obtained justify the feasibility of integrating genotyping for the D294H and I155T variants into risk stratification algorithms to personalize follow-up for patients with CM.

1. Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023; 73(1): 17–48. doi: 10.3322/caac.21763.

2. Arnold M., Singh D., Laversanne M., Vignat J., Vaccarella S., Meheus F., Cust A.E., de Vries E., Whiteman D.C., Bray F. Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040. JAMA Dermatol. 2022; 158(5): 495–503. doi: 10.1001/jamadermatol.2022.0160.

3. Carlino M.S., Larkin J., Long G.V. Immune checkpoint inhibitors in melanoma. Lancet. 2021; 398(10304): 1002–14. doi: 10.1016/S01406736(21)01206-X.

4. Su D.G., Djureinovic D., Schoenfeld D., Marquez-Nostra B., Olino K., Jilaveanu L., Kluger H. Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma. JCO Precis Oncol. 2024; 8: e2300702. doi: 10.1200/PO.23.00702.

5. Mun Y., Kim W., Shin D. Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects. Int J Mol Sci. 2023; 24(15): 12152. doi: 10.3390/ijms241512152.

6. Flori E., Cardinali G., Maresca V. Advances in Pathogenesis and Treatment of Skin Cancer. Int J Mol Sci. 2025; 26(3): 1255. doi: 10.3390/ijms26031255.

7. Tafreshi N.K., Doligalski M.L., Tichacek C.J., Pandya D.N., Budzevich M.M., El-Haddad G., Khushalani N.I., Moros E.G., McLaughlin M.L., Wadas T.J., Morse D.L. Development of Targeted Alpha Particle Therapy for Solid Tumors. Molecules. 2019; 24(23): 4314. doi: 10.3390/molecules24234314.

8. Chen S., Han C., Miao X., Li X., Yin C., Zou J., Liu M., Li S., Stawski L., Zhu B., Shi Q., Xu Z.X., Li C., Goding C.R., Zhou J., Cui R. Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads. Nat Commun. 2019; 10(1): 877. doi: 10.1038/s41467-019-08691-3.

9. Swope V.B., Starner R.J., Rauck C., Abdel-Malek Z.A. Endothelin-1 and α-melanocortin have redundant effects on global genome repair in UVirradiated human melanocytes despite distinct signaling pathways. Pigment Cell Melanoma Res. 2020; 33(2): 293–304. doi: 10.1111/pcmr.12823.

10. Yang M., Brage S.E., Lapins J., Grozman V., Svedman F.C., Höiom V., Helgadottir H. Germline MC1R Variant Status and Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Melanoma. Pigment Cell Melanoma Res. 2025; 38(5): e70050. doi: 10.1111/pcmr.70050.

11. Fiasconaro C.A., Carbone A., Giordano S., Cavallo F., Fava P., Pasini B., Yakymiv Y., Marchisio S., Quaglino P., Ribero S., Roccuzzo G. Germline Non-CDKN2A Variants in Melanoma and Associated Hereditary Cancer Syndromes. Diseases. 2025; 13(6): 180. doi: 10.3390/diseases13060180.

12. Wu X., Fu S., Liu Y., Luo H., Li F., Wang Y., Gao M., Cheng Y., Xie Z. NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice. J Neuroinflammation. 2019; 16(1): 192. doi: 10.1186/s12974-019-1591-4.