Applying GEP to Melanoma Detection

How can GEP be applied to melanoma diagnosis and treatment? Darrel Rigel, MD, MS, answers these questions and dives into the data at Fall Clinical Dermatology Conference 2021.

Genetic expression profiling (GEP) may be helpful to physicians in melanoma diagnosis. Darrel S. Rigel, MD, MS, a clinical professor and director of the Melanoma Surveillance Clinic at the Mount Sinai Icahn School of Medicine, New York, New York, postulated the accuracy of melanoma diagnosing at the Fall Clinical Dermatology Conference 2021, held October 21 to 24 in Las Vegas, Nevada.1 In his presentation, Rigel explained the potential of the technique.

He quoted a 2017 study2 in which a noninvasive pigmented lesion assay (PLA) using a 2-GEP technique was evaluated in 555 pigmented lesions (157 training and 398 validation samples) that were obtained via adhesive patch biopsy. The technique searches for either a Long Intergenic Non-Coding (LINC) or Preferentially Expressed Antigen in Melanoma (PRAME) gene and determines melanoma from nonmelanoma samples with a 91% sensitivity and a specificity of 69% with a 95% confidence interval. The conclusion of this trial was assay can classify pigmented lesions into melanoma and nonmelanoma groups and may serve as a tool to help with diagnostic challenges.

Newer research could also support this claim, Rigel continued. In a 2021 trial,3 3,418 lesions were tested using 2-GEP by 90 licensed clinicians. The median patient age was 48 years with 62% female and 39% male patients. Of the 3,418 lesions, 324 (9.48%) were determined to be positive by 2-GEP testing—90.5% avoided unnecessary biopsy—and 316 were biopsied (97.5%) with 313 pathology reports available for analysis. Of the 316 biopsied lesions, 18.7% were melanoma and 43% were dysplastic nevi which was determined histopathologically.

Of the melanomas and dysplastic nevi:

  • 134/195 (61.7%) expressed a single gene (L+/P- or L-/P+)
  • 61/195 (31.3%) expressed both genes (L+/P+)

When focusing solely on the melanomas, it was found:

  • 31/59 (52.5%) confirmed melanomas expressed a single gene (L+/P- or L-/P+)
    • 14/59 (23.7%) expressed LINC only (L+/P-)
    • 17/59 (28.8%) expressed PRAME only (L-/P+)
  • 28/59 (47.5%) confirmed melanomas expressed both genes (L+/P+)

Rigel quoted the study authors, “Lesions clinically suspicious of melanoma exist along a spectrum of genomic atypia... there is a correlation between increasing genomic atypia and melanoma-associated pathology atypia.”

Rigel detailed a trial in which GEP was shown to increases both the real-world negative predictive value (NPV) and positive predictive value (PPV) of the melanoma diagnostic pathway and reduced biopsy burden.

In a study,4 researchers investigated 1,233 2-GEP-negative pigmented lesions for evidence of malignancy for up to 36 months and also retested a separate prospective cohort of 302 2-GEP-negative lesions up to 2 years after initial testing. These results demonstrated that in this real-world intended use population, the 2-GEP has an NPV of greater than 99%, confirming the high NPV established in previous clinical studies.

A PPV of 18.7% was determined by using a US-based registry of 3,418 2-GEP-tested cases, identifying the melanoma diagnoses based off the 2-GEP-positive lesions. Of the 5,993 lesions tested with the 2-GEP from both the TRUST study and registry cases, most 2-GEP tests were negative and not subjected to surgical biopsy. The 2-GEP test reduced surgical biopsies by 83.5% to 86.5% in the TRUST study and US registry cohorts, respectively (N=5993).

Rigel went on to describe the DermTech PLA kit, which uses 2-GEP analysis. First the doctor holds an initial appointment to assess the patient’s skin. Then, if needed, the physician orders the PLA and the kit will be shipped directly to the patient. After, a follow up appointment needs to be scheduled so the doctor can supervise the patient collecting the sample. This could be done via virtual appointment. Finally, the lab will analyze the sample and report the results to the physician.

There is an additional test besides 2-GEP that uses genetics. A 3-GEP test (PLAplus) also tests for the Telomerase Reverse Transcriptase (TERT) gene. Rigel explained that TERT promoter mutations are detected in 70% of histopathologically confirmed melanomas5 and 97% of histopathologically confirmed melanomas express TERT and/or LINC and/or PRAME.6

Mutations in the cell can lead to oncogenesis through functional increases in TERT protein, telomerase activity, telomere length, cell immortalization, and proliferation, according to Rigel. It is associated with histopathologic features of aggressiveness and poor survival in melanoma.

The 3-GEP data showed a 97% sensitivity with a 62% specificity, leading to a 99.6% NPV.

Rigel concluded the presentation with 3 points:

  1. Efficiency and accuracy are critical in MM diagnosis.
  2. Genomics is impacting this area.
  3. 2-GEP and 3-GEP testing can be a useful adjunct to this process in a clinical setting.


Rigel is on the advisory board, honoraria, and investigator for Castle BioSciences. he is a consultant for DermTech.


  1. Rigel, D. Apply GEP to melanoma detection. Presented at: Fall Clinical Dermatology Conference 2021; October 21-24, 2021; Las Vegas, Nevada and virtual.
  2. Gerami P, Yao Z, Polsky D, et al. Development and validation of a noninvasive 2-gene molecular assay for cutaneous melanoma. Journal of the American Academy of Dermatology. 2017;76(1):114-120.e2. doi:10.1016/j.jaad.2016.07.038
  3. Brouha B, Ferris L, Skelsey M, et al. Genomic atypia to enrich melanoma positivity in biopsied lesions: gene expression and pathology findings from a large u. S. Registry study. SKIN The Journal of Cutaneous Medicine. 2021;5(1):13-18. doi:10.25251/skin.5.1.3
  4. Skelsey M, Brouha B, Rock J, et al. Non-invasive detection of genomic atypia increases real-world npv and ppv of the melanoma diagnostic pathway and reduces biopsy burden. SKIN The Journal of Cutaneous Medicine. 2021;5(5):512-523. doi:10.25251/skin.5.5.9
  5. Cullison SRJ, Jansen B, Yao Z, Ferris LK. Risk stratification of severely dysplastic nevi by non-invasively obtained gene expression and mutation analyses. SKIN The Journal of Cutaneous Medicine. 2020;4(2):124-129. doi:10.25251/skin.4.2.5
  6. Ferris LK, Moy RL, Gerami P, et al. Noninvasive analysis of high-risk driver mutations and gene expression profiles in primary cutaneous melanoma. J Invest Dermatol. 2019;139(5):1127-1134. doi:10.1016/j.jid.2018.10.041