DNA methylation variations of DNA damage response correlate survival and local immune status in melanomas

Aim We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. Material & methods Different melanoma cohorts with molecular and clinical data were included. Results Hierarchical clustering utilizing different combinations of DDR‐relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4‐CpG risk‐score signature for predicting survival and immunotherapy response. Conclusion Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response. The present study proposed a series of DNA damage response (DDR) DNA methylation‐based subtypes of melanomas with distinct prognosis, transcriptional function profiles of DDR and immunity, and immunotherapy response. Those novel epigenetic DDR classification schemes for melanomas not only provide ideal models for illustrating the interrelationship among DNA methylation, DDR function, local tumor immunity, immunotherapy efficacy, and cancer prognosis but also provide useful information for predicting immunotherapy response and guiding the combinatorial use of epigenetic therapy, DDR inhibitors, DNA‐damaging agents and immunotherapy.