Melanoma Mutations

MUTATIONS are common in melanoma, and they are often mutually exclusive. A patient generally has only one mutation, namely: BRAF (50%), NRAS (13.25%), MEK1 (6%), KIT (2.6%), CTNNB1 (2%–3%), GNA11 (2%), or GNAQ (1%).

THE MOST CRITICAL mutation in melanoma is BRAF. More than 90% of BRAF mutations are located at codon 600; of them, more than 90% are at V600E; about 5% are at V600K; and a few are at V600R, V600E2, or V600D.

Three BRAF/MEK inhibitor combinations are available for these patients: vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and dabrafenib (Tafinlar) plus trametinib (Mekinist) are approved by the U.S. Food and Drug Administration; encorafenib plus binimetinib are in clinical trials.

MUTATIONS AND AMPLIFICATIONS in KIT are seen in mucosal, acral, or chronically sun-damaged melanoma. These patients may respond to a KIT inhibitor such as imatinib.

Companion diagnostic assays are available for vemurafenib— the cobas 4800 BRAF V600 mutation test—and for dabrafenib—the THxID assay, which tests for V600E and V600K. Both are PCR-based, but more comprehensive testing can be achieved with next-generation sequencing, which can identify all the relevant mutations.

More than 90% of melanomas diagnosed in the clinic are cutaneous. Cutaneous melanomas often harbor BRAF mutations (40%–50%) and to a lesser degree NRAS mutations (15%–20%). KIT aberrations are occasionally seen as well, usually arising in sun-damaged sites.

Much less common are mucosal and acral melanomas—ie, lesions in vaginal, anal, sinonasal, and palmar or plantar sites. In these patients, BRAF and NRAS mutations are rare, but 15% to 40% of patients will have KIT mutations.

Even less common are uveal melanomas, accounting for 5%. More than 80% of these patients have GNAQ or GNA11 mutations, and they lack targeted drugs. Primary uveal therapy is local: brachytherapy, proton beam, and enucleation. Generally, the overall prognosis is poor, with 5- and 10-year cumulative metastasis rates of 25% and 34%, respectively. Median time from diagnosis to death is 6 months.

Metastatic disease in uveal melanoma goes almost exclusively to the liver. In determining prognosis of uveal melanoma, TNM (tumor, nodal, metastasis) staging is not particularly helpful, but chromosome analysis is informative: 

  • BRCA1-associated protein (BAP1 gene), located on chromosome 3: Monosomy is associated with poor prognosis. 
  • Chromosome 8q: Gain is associated with poor prognosis.
  • Chromosome 6p: Gain is associated with better survival.
  • Chromosome 6q: Loss is associated with better survival.

Polymerase chain reaction (PCR)-based gene-expression profiling that tests for 15 different genes has been able to separate uveal melanoma into two classes. Class 1 patients have more than a 95% chance of being free of metastasis at 5 years, but class 2 patients have less than a 20% chance.

Reference

Yushak Melinda, Melanoma Mutations: What You Need to Know, The ASCO Post, November 25, 2017

http://www.ascopost.com/issues/november-25-2017/melanoma-mutations-what-you-need-to-know/

 

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