Introduction Skin that is exposed to chronic UV presents a distinct pattern of structural degradation compared to age-matched, sun-protected skin. The morphological change underpinning chronic UV cutaneous damage is collagen degradation of the dermis. Molecularly, UV-aged skin accumulates primarily UV-driven mutations, in contrast to UV-protected skin where mutations are rare. The enrichment of mutations in non-neoplastic, aged cells is a defining feature of skin ageing. Melanoma increases with age, and most patients who die are older than 55. Age is the most important independent marker of adverse outcome together with tumor thickness. Old patients commonly present melanoma over chronic UV-damaged skin with a high number of mutations, and some studies suggest these may be linked to better outcome. Here we explore the relationship between tumor mutation burden, stromal DNA damage and outcome of elderly primary melanoma patients.
Results We examined the types of mutations contributing to the somatic mutation load in melanoma. We inferred the signature linked to accumulated UV DNA damage (signature 7 from COSMIC), as well as the intrinsic, proliferation and age-related signature (signature 1). Logistic regression models of signature 1 and 7 demonstrate both correlate with age, and elderly patients are at higher risk of death in this cohort. These data are in contrast to studies suggesting melanomas arising at sites of chronic sun exposure (CSE) have an improved survival, and studies showing higher mutation rates in melanoma are linked to better outcome. To test this, we generated isogenic melanoma cell lines with high versus low UV-mutation burden, and found CSE melanoma cells were more proliferative, invasive and migratory. We next investigated if a higher rate of UV damage to dermal fibroblasts affects outcome by generating isogenic CSE and noCSE dermal fibroblast lines and found melanoma cells exposed to noCSE fibroblasts were more invasive than melanoma cells exposed to CSE fibroblasts. We validated this in human dermal fibroblasts. Dermal fibroblasts from protected sites presented few mutations and promoted melanoma invasion, whereas fibroblasts from chronic UV skin had more mutations and did not drive melanoma invasion. Furthermore, CSE fibroblasts with many mutations present a distinct expression and metabolic profile linked to the sunburn response genes that blocks melanoma invasion. We validated our findings in 490 specimens of elderly primary cutaneous melanoma patients. Multivariate analysis shows the presence of degraded collagen, a surrogate marker of UV damage, is an independent marker of better outcome in the elderly population.
Discussion Our study shows UV-driven damage in aged dermal fibroblasts protects from primary melanoma invasion and humans with extensive dermal UV damage present an improved outcome. Our finding that excessive UV can improve outcome of patients with melanoma is a paradigm shift.
Citation Format: Eduardo Nagore, Katharina Roeck, Timothy Budden, Stephen P. Smith, Sarah Craig, Jean Krutmann, Martin Lotz, Simon Furney, Amaya Viros. Chronic UV damage of the stroma improves melanoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2022.