Melanoma: What Do All the Mutations Mean?

Overview

Journal Cancer

Publisher Wiley

Specialty Oncology

Date 2018 Apr 18

PMID 29663336

Citations 82

Authors

Elizabeth J Davis

Douglas B Johnson

Jeffrey A Sosman

Sunandana Chandra

Affiliations

Soon will be listed here.

Abstract

Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both "driver" and "passenger" genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high-frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.

Citing Articles

Advancements in Melanoma Treatment: A Review of PD-1 Inhibitors, T-VEC, mRNA Vaccines, and Tumor-Infiltrating Lymphocyte Therapy in an Evolving Landscape of Immunotherapy.

Mehta A, Motavaf M, Nebo I, Luyten S, Osei-Opare K, Gru A J Clin Med. 2025; 14(4).

PMID: 40004731 PMC: 11856346. DOI: 10.3390/jcm14041200.

Crosstalk Between nNOS/NO and COX-2 Enhances Interferon-Gamma-Stimulated Melanoma Progression.

Patel A, Tong S, Roosan M, Syed B, Awasthi A, Silverman R Cancers (Basel). 2025; 17(3).

PMID: 39941844 PMC: 11816268. DOI: 10.3390/cancers17030477.

The anti-melanoma roles and mechanisms of tricholoma isoflavone derivative CA028.

Liang C, Jiang J, Li J, Lin X, Huang W, Lai K NPJ Sci Food. 2025; 9(1):4.

PMID: 39788977 PMC: 11718060. DOI: 10.1038/s41538-025-00370-6.

Gender and melanoma subtype-based prognostic implications of MUC16 and TTN co-occurrent mutations in melanoma: A retrospective multi-study analysis.

Kodali N, Alomary S, Bhattaru A, Eldaboush A, Schwartz R, Lipner S Cancer Med. 2024; 13(17):e70199.

PMID: 39240165 PMC: 11378355. DOI: 10.1002/cam4.70199.

Molecular Susceptibility and Treatment Challenges in Melanoma.

Kolathur K, Nag R, Shenoy P, Malik Y, Varanasi S, Angom R Cells. 2024; 13(16).

PMID: 39195270 PMC: 11352263. DOI: 10.3390/cells13161383.

References

Shaw A, Ou S, Bang Y, Camidge D, Solomon B, Salgia R . Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014; 371(21):1963-71. PMC: 4264527. DOI: 10.1056/NEJMoa1406766. View

Spranger S, Luke J, Bao R, Zha Y, Hernandez K, Li Y . Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc Natl Acad Sci U S A. 2016; 113(48):E7759-E7768. PMC: 5137753. DOI: 10.1073/pnas.1609376113. View

Chalmers Z, Connelly C, Fabrizio D, Gay L, Ali S, Ennis R . Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017; 9(1):34. PMC: 5395719. DOI: 10.1186/s13073-017-0424-2. View

Maldonado J, Fridlyand J, Patel H, Jain A, Busam K, Kageshita T . Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003; 95(24):1878-90. DOI: 10.1093/jnci/djg123. View

Ascierto P, McArthur G, Dreno B, Atkinson V, Liszkay G, Di Giacomo A . Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016; 17(9):1248-60. DOI: 10.1016/S1470-2045(16)30122-X. View

Cirenajwis H, Lauss M, Ekedahl H, Torngren T, Kvist A, Saal L . NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics. Mol Oncol. 2017; 11(4):438-451. PMC: 5527484. DOI: 10.1002/1878-0261.12050. View

Shi H, Hugo W, Kong X, Hong A, Koya R, Moriceau G . Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2013; 4(1):80-93. PMC: 3936420. DOI: 10.1158/2159-8290.CD-13-0642. View

Menzies A, Haydu L, Visintin L, Carlino M, Howle J, Thompson J . Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012; 18(12):3242-9. DOI: 10.1158/1078-0432.CCR-12-0052. View

Moriceau G, Hugo W, Hong A, Shi H, Kong X, Yu C . Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell. 2015; 27(2):240-56. PMC: 4326539. DOI: 10.1016/j.ccell.2014.11.018. View

10.

Long G, Weber J, Infante J, Kim K, Daud A, Gonzalez R . Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol. 2016; 34(8):871-8. DOI: 10.1200/JCO.2015.62.9345. View

11.

Verweij J, Casali P, Zalcberg J, Lecesne A, Reichardt P, Blay J . Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364(9440):1127-34. DOI: 10.1016/S0140-6736(04)17098-0. View

12.

Atkins M, Lotze M, Dutcher J, Fisher R, Weiss G, Margolin K . High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999; 17(7):2105-16. DOI: 10.1200/JCO.1999.17.7.2105. View

13.

Dong J, Phelps R, Qiao R, Yao S, Benard O, Ronai Z . BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003; 63(14):3883-5. View

14.

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky J, Desrichard A . Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189-2199. PMC: 4315319. DOI: 10.1056/NEJMoa1406498. View

15.

Sosman J, Kim K, Schuchter L, Gonzalez R, Pavlick A, Weber J . Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-14. PMC: 3724515. DOI: 10.1056/NEJMoa1112302. View

16.

Tsao H, Goel V, Wu H, Yang G, Haluska F . Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004; 122(2):337-41. PMC: 2586668. DOI: 10.1046/j.0022-202X.2004.22243.x. View

17.

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

18.

Rosenberg S, Packard B, Aebersold P, Solomon D, Topalian S, TOY S . Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988; 319(25):1676-80. DOI: 10.1056/NEJM198812223192527. View

19.

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

20.

Jin S, Chun S, Choi Y, Kweon S, Jung S, Shim H . BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol. 2012; 133(2):579-82. DOI: 10.1038/jid.2012.338. View