Melanoma is an aggressive malignancy with a poor prognosis.,Current studies show that imatinib treatment is a promising approach in treating advanced melanoma patients harboring c-Kit mutations or amplifications.,We retrospectively analyzed the clinical medical records of 78 patients with metastatic melanoma harboring c-Kit mutations or amplifications.,These patients were treated with imatinib at a dose of 400 mg/day continuously unless intolerable toxicities or disease progression occurred.,Endpoints for exploration included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease of control rate (DCR).,The median OS and PFS of all patients were 13.1 and 4.2 months, respectively.,ORR and DCR were 21.8% and 60.3%, respectively.,The survival time of patients who achieved partial response or stable disease was significantly superior to those with disease progression.,Cox regression analysis showed that patients with M1c stage, subtype of cutaneous melanoma, or elevated LDH level (>upper limit of normal) had higher hazard ratios for overall survival.,Our study, combined with those studies targeting patients with a c-Kit alteration, validates the role of imatinib as an important and promising therapeutic agent in the treatment of patients with advanced melanoma.
During development, enhancers play pivotal roles in regulating gene expression programs; however, their involvement in cancer progression has not been fully characterized.,We performed an integrative analysis of DNA methylation, RNA-seq, and small RNA-seq profiles from thousands of patients, including 25 diverse primary malignances and seven body sites of metastatic melanoma.,We found that enhancers are consistently the most differentially methylated regions (DMR) as cancer progresses from normal to primary tumors and then to metastases, compared to other genomic features.,Remarkably, identification of enhancer DMRs (eDMRs) enabled classification of primary tumors according to physiological organ systems, and in metastasis eDMRs are the most correlated with patient outcome.,To further understand the eDMR role in cancer progression, we developed a model to predict genes and microRNAs that are regulated by enhancer and not promotor methylation, which shows high accuracy with chromatin architecture methods and was experimentally validated.,Interestingly, among all metastatic melanoma eDMRs, the most correlated with patient survival were eDMRs that “switched” their methylation patterns back and forth between normal, primary, and metastases and target cancer drivers, e.g., KIT.,We further demonstrated that eDMR target genes were modulated in melanoma by the bone metastasis microenvironment, suggesting that eDMRs respond to microenvironmental cues in metastatic niches.,Our findings that aberrant methylation in cancer cells mostly affects enhancers, which contribute to tumor progression and cancer cell plasticity, will facilitate development of epigenetic anticancer approaches.