We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients.
Bibliographical noteFunding Information:
We thank Ting Tu, Daniel Lackaye, Michelle Ma, and Holly Greenwald for the management of the clinical information of the Interdisciplinary Melanoma Cooperative Group (IMCG) patients. We thank Erica Friedman for her help with real-time PCR. PJC was partially supported by the Clinical Translational Science Center (CTSC) grant UL1-RR024996. This work was supported by the Chemotherapy Foundation, the Elsa U. Pardee Foundation, and the National Cancer Institute Cancer Center Support grant 5 P30 CA 016087-27.