Genome-Wide Methylation Profiles of Primary and Matched Distant Metastasis: Insights from the Dutch Early-Stage Melanoma (D-Esmel) Study

Background Early-stage (stage I-II) cutaneous melanoma accounts for the majority of melanoma diagnoses, but more than 40% of patients who die due to melanoma were initially diagnosed with an early-stage melanoma. 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 samples from the Dutch Early-Stage Melanoma (D-ESMEL) study, representing case-control sets where the primary melanoma of each metastatic case is matched to a primary melanoma of a control based on known clinical risk factors. Matched distant metastasis 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. 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 We identified 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.