Genome-wide methylation profiles of primary and matched distant metastasis: insights from the Dutch Early-Stage melanoma (D-ESMEL) study

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BACKGROUND: Early-stage (stage I-II) cutaneous melanoma accounts for the majority of melanoma diagnoses. However, more than 40% of patients who die due to melanoma were initially diagnosed with an early-stage melanoma. This highlights the current limitations of the Tumor Node Metastasis (TNM) staging and shows that additional biomarkers, prognostic for distant metastasis, need to be identified. METHODS: The aim of this study was to identify prognostic genome-wide methylation markers of metastasized primary early-stage melanomas and retrieving biological insights from its matched distant metastasis. We selected 45 samples from the Dutch Early-Stage Melanoma (D-ESMEL) study, representing case-control sets where the primary melanoma of each metastatic case (n = 15) is matched to a primary melanoma of a control (n = 15) based on known clinical risk factors. Matched distant metastasis (n = 15) were also retrieved. Laser capture microdissection was performed to isolate the tumor tissue, where after a genome-wide methylated DNA sequencing (MeD-seq) was conducted. After quality control, a total of 30 samples were retained for analysis, including 11 controls, 9 cases, and 10 metastatic samples. Differentially methylated regions (DMR) between primary tumors of the cases-control sets and the tumor of the primary case and its metastasis were tested using Chi-squared test with a genome-wide sliding window analysis, as well as a paired t-test in predefined promotor, gene body, and CpG-island regions. RESULTS: MeD-seq analyses did not reveal prognostic methylation markers in primary melanomas, which have additional prognostic value on top of known clinical risk factors after correction for multiple testing. However, exploratory analysis before correction revealed eight protein coding genes with the largest methylation difference between primary melanomas of patients with and without metastasis and between primary melanomas and matched distant metastasis: CYP2E1, PTPRN2, CHCHD2, NDRG2, EDN2, GC, USP17L1, and SERPINB8. CONCLUSION: This study found 8 genes that have been implicated in primary tumors or metastasis of other cancers which require further investigation into their involvement of metastasis in melanoma.

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