Noninvasive genomic detection of melanoma

Abstract

Background: Early detection and treatment of melanoma is important for optimal clinical outcome, leading to biopsy of pigmented lesions deemed suspicious for the disease. The vast majority of such lesions are benign. Thus, a more objective and accurate means for detection of melanoma is needed to identify lesions for excision.

Objectives: To provide proof-of-principle that epidermal genetic information retrieval (EGIR™; DermTech International, La Jolla, CA, U.S.A.), a method that noninvasively samples cells from stratum corneum by means of adhesive tape stripping, can be used to discern melanomas from naevi.

Methods: Skin overlying pigmented lesions clinically suspicious for melanoma was harvested using EGIR. RNA isolated from the tapes was amplified and gene expression profiled. All lesions were removed for histopathological evaluation.

Results: Supervised analysis of the microarray data identified 312 genes differentially expressed between melanomas, naevi and normal skin specimens (P<0·001, false discovery rate q<0·05). Surprisingly, many of these genes are known to have a role in melanocyte development and physiology, melanoma, cancer, and cell growth control. Subsequent class prediction modelling of a training dataset, consisting of 37 melanomas and 37 naevi, discovered a 17-gene classifier that discriminates these skin lesions. Upon testing with an independent dataset, this classifier discerned in situ and invasive melanomas from naevi with 100% sensitivity and 88% specificity, with an area under the curve for the receiver operating characteristic of 0·955.

Conclusions: These results demonstrate that EGIR-harvested specimens can be used to detect melanoma accurately by means of a 17-gene genomic biomarker.

Fig 1

Hierarchical clustering analysis of differentially expressed genes among melanomas, naevi and normal skin. These 312 genes determined from microarray analysis of epidermal genetic information retrieval specimens differentiate melanoma from atypical naevi and normal skin (P<0·001, false discovery rate q<0·05).

Fig 2

Ingenuity Pathway Analysis of epidermal genetic information retrieval-harvested melanoma specimens identifies overexpressed genes involved in melanocyte development and pigmentation. Melanocyte development and pigmentation is primarily regulated by microphthalmia-associated transcription factor (MITF), which is controlled mainly through the melanocyte-stimulating hormone (MSH) signalling pathway that includes adenylate cyclase 2 (ADCY2), sex determining region Y-box 10 (SOX10) and paired box 3 (PAX3) as well as the v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (Kit) signalling pathway. Tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and dopachrome tautomerase (DCT) are activated by MITF and are also involved in skin pigmentation.

Fig 3

Hierarchical clustering of melanomas and naevi using the 17-gene classifier. Shown are data from the training set of 37 melanomas and 37 naevi. The specimen denoted by the arrow was called a Clark naevus on initial pathological review, but was deemed a melanoma by the 17-gene classifier. The presence of invasive melanoma was detected in this biopsy by both the primary and central dermatopathologists upon re-review of the serially sectioned specimen.