The Association of Residential Altitude on the Molecular Profile and Survival of Melanoma: Results of an Interreg Study.

Eleonora De Martino,Davide Brunetti,Iris Zalaudek,Emina Jukic,Federica Rao,Klaus Eisendle,Giorgio Stanta,Johannes Zschocke,Carla Nobile,Serena Bonin,Georg Weinlich,Bernhard Zelger,Guido Mazzoleni,Wolfram Jaschke,Matthias Schmuth,Vincenzo Canzonieri,Fabrizio Zanconati,Claudio Conforti

doi:10.3390/cancers12102796

Abstract

Simple SummaryEnvironmental factors such as UVR exposure and altitude of residence can contribute to the development of cutaneous melanoma. We hereby report that altitude of residence significantly associates with the molecular profiling of CM and melanoma specific survival. The fact that different miRNAs and transcriptomic profile vary with different geographical areas and residences altitude could support for possible regulatory mechanisms induced by environmental conditions, such as hypoxic environment and/or higher UVR exposure.Cutaneous melanoma (CM) incidence is rising worldwide and is the primary cause of death from skin disease in the Western world. Personal risk factors linked to environmental ultraviolet radiation (UVR) are well-known etiological factors contributing to its development. Nevertheless, UVR can contribute to the development of CM in different patterns and to varying degrees. The present study aimed at investigating whether altitude of residence can contribute to the development of specific types of CM and/or influence its progression. To this aim, 306 formalin-fixed and paraffin-embedded (FFPE) tissues from primary CM diagnosed in different geographical areas were submitted to B-RAF proto-oncogene serine/threonine kinase (BRAF) and N-RAS proto-oncogene GTPase (NRAS) mutational status detection and mRNA and miRNA profiling by qPCR. Genes were chosen for their functions in specific processes, such as immune response (CD2, PDL1, or CD274) and pigmentation (MITF, TYRP1, and TRPM1). Furthermore, four microRNAs, namely miR-150-5p, miR-155-5p, miR-204-5p, and miR-211-5p, were included in the profiling. Our results highlight differences in the gene expression profile of primary CM with respect to the geographical area and the altitude of residence. Melanoma-specific survival was influenced by the gene expression of mRNA and miRNAs and varied with the altitude of patients’ residence. In detail, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p. Since miRNAs are highly regulated by reactive oxygen species, it is possible that different regulatory mechanisms characterize CMs at different altitudes due to the different environment and UVR intensity.

Highlights

Cutaneous melanoma (CM) incidence is rising worldwide and continues to be the primary cause of death from skin disease in the Western world [1]
Our results show that miR-211-5p favorably influenced melanoma-specific survival but did not influence the overall survival
The heterogeneous cohort was composed of patients who had been living in different geographic areas and at different altitudes of residence

Summary

Introduction

Cutaneous melanoma (CM) incidence is rising worldwide and continues to be the primary cause of death from skin disease in the Western world [1]. Personal risk factors, including family history, multiple moles, fair skin, blue eyes, red hair, and freckles, together with environmental UV exposure are well-known etiological factors contributing to the development of CM [2,3]. CM is not a homogeneous disease; there are different types of CM and UV radiation (UVR) can contribute to the development of melanoma in different ways and to varying degrees [2]. The same UVR that reaches the Earth’s surface can vary according to different variables. Altitude is a further contributing factor, with an emission increment of 10−12% for every 1000 m elevation [4]

Objectives

Methods

Results

Conclusion