Clock-like Mutation Signature May Be Prognostic for Worse Survival Than Signatures of UV Damage in Cutaneous Melanoma

SIMPLE SUMMARY: Although immunotherapy and targeted therapy have dramatically improved melanoma survival, some patients rapidly progress and decease within a few months after a stage IV diagnosis. Up until now, pathological, clinical and biological markers are known prognostic factors for survival of melanoma, while still no prognostic genetic alterations have been identified. Therefore, we aimed to find genetic alterations that predict a short or long survival by sequencing 190 melanoma-related genes of tumor material from 79 patients to contribute to the growing body of knowledge regarding mutational profiling. While no individual gene mutations or combinations of alterations could be linked to overall survival in our study cohort, a clock-like mutational signature according to the Catalog of Somatic Mutations in Cancer (COSMIC) was associated with poor survival whereas a UV mutational signature was prognostic for a longer survival. Those findings are congruent with earlier findings of other authors. Therefore, the prognostic relevance of mutational signatures must be further evaluated in prospective studies. ABSTRACT: Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort’s mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.