Abstract
Primary melanoma, a highly aggressive malignancy, exhibits heterogeneity in biologic behaviors, clinical characteristics, metastasis potential and mortality. The present study sought to identify the molecular signatures that define a subgroup of primary melanomas with high risks of metastasis and mortality. First, we identified the markers that best differentiated metastatic melanomas from primary melanomas by examining the expression of seven previously reported biomarkers (BRAF, Dicer, Fbw7, KAI1, MMP2, p27 and Tip60) in a training cohort consisting of 145 primary melanomas and 105 metastatic melanomas. KAI1 and p27, both tumor suppressors, emerged as best candidates. Loss of both tumor suppressors occurred in the majority (74.29%) of metastatic melanomas. Further, a subset (metastatic like, or "ML", 33.10%) of primary melanomas also lost these two tumor suppressors. Kaplan-Meier analysis indicated that ML subgroup of primary melanoma patients had much worse 5 year survival compared with other primary melanoma patients (P = 0.002). The result was confirmed in an independent validation cohort with 92 primary melanomas (P = 0.030) and in the combined cohort with 237 melanoma patients (P = 3.00E-4). Additionally, compared to KAI1 and p27 as an individual prognostic marker, the combined signature is more closely associated with melanoma patient survival (P = 0.025, 0.264 and 0.009, respectively). In conclusion, loss of both KAI1 and p27 defines a subgroup of primary melanoma patients with poor prognosis. This molecular signature may help in metastatic melanoma diagnosis and may provide information useful in identifying high-risk primary melanoma patients for more intensive clinical surveillance in the future.
Highlights
Cutaneous melanoma, arising from abnormal proliferation of melanocytes in the epidermis, is one of the most aggressive forms of skin cancer [1]
Univariate analysis showed that BRAF, Dicer, KAI1, P27 and Tip60 were differentially expressed in metastatic melanoma as compared to primary melanoma
Since Fidler first demonstrated the heterogeneity of mouse melanoma cells with respect to metastatic potential in 1973 [41], several genome-wide high-throughput studies have described gene expression signatures to predict metastasis of primary melanoma patients
Summary
Cutaneous melanoma, arising from abnormal proliferation of melanocytes in the epidermis, is one of the most aggressive forms of skin cancer [1]. The treatment of metastatic melanoma has been notably improved by recent development of the specific MAPKinase (BRAFV600E, MEK) inhibitors and the immune checkpoint antibodies (anti-CTLA-4, anti-PD1/PDL1) [36]. Both therapies have shown survival benefit for patients with metastatic melanoma, both regimens have their own limitations [7]. The currently used AJCC (American Joint Committee of Cancer) staging system, which is based on clinical and histological parameters, highly useful as a general guideline for prognostication, cannot precisely define such metastasis/mortality risks in many cases. Sentinel node biopsy has been recommended by AJCC as an important prognostic factor in early stage melanoma. Development of a prognostic assay that could triage high risk primary melanomas will be highly valuable for melanoma management and beneficial for melanoma patients
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