Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure

Abstract

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival. TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.

Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics

“…There are only a few known clinico-genomic factors predicting prognosis in CM ( Gerami et al, 2015 ; Cancer Genome Atlas Network, 2015 ; Garg et al, 2021 ). Our data are consistent with those of previous studies that demonstrated the prognostic implication of the UV signature ( Trucco et al, 2019 ; Pham et al, 2020 ; Vicente et al, 2022 ). One of the characteristics of the UV-low cluster is lower mutational and higher CNA burdens, which is similar to the genomic profiles of acral melanoma, a rare subtype of melanoma that has a poorer prognosis than CM ( Liang et al, 2017 ; Rabbie et al, 2019 ; Newell et al, 2020 ).…”

“…Interestingly, the key genomic alterations of acral melanomas described in a previous study ( Newell et al, 2020 ) (such as the highest proportion of triple-WT tumors, common KIT alterations, and lower frequencies of BRAF/RAS hotspot mutations) are consistent with the characteristics of the UV-low cluster in this study. In line with our findings, another recent study reported results from epigenomic mapping which also suggest that UV-low CMs more closely resemble acral melanomas rather than UV-high CMs ( Vicente et al, 2022 ).…”

“…In our study, the “Hypo-methylated” subtype comprised a significantly higher proportion of the UV-high cluster compared to the UV-low cluster, indicating the possibility of distinct DNA methylation profiles. A previous study suggested that distinct DNA methylation profiles between UV-high and UV-low CMs may play a role in immunomodulation and alteration of immune cell composition ( Vicente et al, 2022 ).…”

“…Acral and mucosal melanomas are known to harbor low UV signatures and distinct clinico-genomic features ( Hayward et al, 2017 ; Rabbie et al, 2019 ; Newell et al, 2020 ). Recent genomic studies have revealed that CMs with a high UV signature typically display better prognosis ( Trucco et al, 2019 ; Vicente et al, 2022 ) and immunotherapeutic outcomes ( Pham et al, 2020 ; Dousset et al, 2021 ). Recently, a multi-omics study revealed that CMs with a low UV signature harbored distinct epigenetic profiles in regulatory regions and immunological pathways resembling acral melanoma ( Vicente et al, 2022 ).…”

“…Recent genomic studies have revealed that CMs with a high UV signature typically display better prognosis ( Trucco et al, 2019 ; Vicente et al, 2022 ) and immunotherapeutic outcomes ( Pham et al, 2020 ; Dousset et al, 2021 ). Recently, a multi-omics study revealed that CMs with a low UV signature harbored distinct epigenetic profiles in regulatory regions and immunological pathways resembling acral melanoma ( Vicente et al, 2022 ). However, the mutational signatures and clinico-genomic characteristics of CMs with low UV signatures have not been fully characterized yet.…”