Next-Generation Sequencing for Cutaneous Melanoma

Castle Biosciences’ DecisionDx-CMSeq is a 3-gene test that uses next-generation sequencing (NGS) to identify somatic mutations relevant to cutaneous melanoma in melanoma tumor tissue. The test includes hotspot mutations in the genes BRAF, NRAS, and KIT.

Mutations in these genes are important to help inform therapy choices for melanoma patients in the adjuvant and metastatic settings, including clinical trial opportunities. There are FDA-approved therapies that target the BRAF mutation and downstream pathways in metastatic melanoma. The FDA has also approved adjuvant targeted combination therapy for resected Stage III melanoma based on recent evidence (Long 2017). Ongoing clinical trials evaluating new targeted therapies may also enroll patients with BRAF-, NRAS- or KIT-mutant melanoma.

The DecisionDx-CMSeq test can be ordered on formalin-fixed paraffin-embedded (FFPE) primary tumor tissue in conjunction with the DecisionDx-Melanoma gene expression profile (GEP) test to obtain both a prognostic and therapeutic profile of the tumor at the same time. The DecisionDx-CMSeq test can also be ordered separately on FFPE tissue from the primary tumor, lymph node, or metastasis.

BRAF, NRAS, KIT Mutations In Melanoma: Current Clinical Utility

In melanoma, tumor growth is predominantly driven by signaling in the mitogen-activated protein kinase (MAPK) pathway (Schadendorf 2015), which includes proteins encoded by the NRASBRAF, and KIT genes. In some melanoma tumors, mutations in members of the MAPK signaling pathway result in constitutively active signaling. Targeted therapies, such as BRAF and MEK inhibitors, are used to block an overactive MAPK pathway. They are often used in combination to target multiple components of the pathway in an effort to overcome resistance that can result with monotherapy.

Ordering DecisionDx-CMSeq

The DecisionDx-CMSeq test can be ordered for FFPE primary melanoma tumor tissue in conjunction with the DecisionDx-Melanoma GEP test. DecisionDx-CMSeq can also be ordered as a standalone test. If ordered together, all necessary slides will be requested at the same time. If ordered separately at different times, there will be an additional request of slides for sequencing. The DecisionDx-CMSeq test can also be ordered for FFPE metastatic tissue, including lymph node metastases.

To order the DecisionDx-CMSeq test, please complete the order form and check the “Additional Testing: DecisionDx-CMSeq Sequencing Test” option in the test menu.

Castle Biosciences, Inc. will bill your patient’s insurance for the DecisionDx-CMSeq test.

Understanding the DecisionDx-CMSeq Results

The DecisionDx-CMSeq report will tell you if clinically relevant mutations (variants) were found in the three genes targeted by the test. For each mutation found, the report will describe:

  • Genomic location of the mutation (where in the gene did it occur)
  • Type of mutation (missense, nonsense, etc.)
  • Functional change that occurs because of the mutation (i.e. an amino acid change in the protein)
  • Frequency that the mutation was detected in the sample (variant allele frequency)
  • Potential consequences of that mutation on gene function and relevant literature references

Tier and Level of Evidence, as defined by the College of American Pathologists (CAP), the American Society of Clinical Oncology (ASCO), and Association for Molecular Pathologists (AMP) guidelines (Li 2017), will also be reported for each mutation.


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