TY - JOUR
T1 - The association of residential altitude on the molecular profile and survival of melanoma
T2 - Results of an interreg study
AU - De Martino, Eleonora
AU - Brunetti, Davide
AU - Canzonieri, Vincenzo
AU - Conforti, Claudio
AU - Eisendle, Klaus
AU - Mazzoleni, Guido
AU - Nobile, Carla
AU - Rao, Federica
AU - Zschocke, Johannes
AU - Jukic, Emina
AU - Jaschke, Wolfram
AU - Weinlich, Georg
AU - Zelger, Bernhard
AU - Schmuth, Matthias
AU - Stanta, Giorgio
AU - Zanconati, Fabrizio
AU - Zalaudek, Iris
AU - Bonin, Serena
N1 - Funding Information:
This was a population-based retrospective study. The study was part of the MEMS project (www.mems-interreg.eu) funded by the European Union’s Interreg V-A Italia-Austria 2014−2020 program. Participating centers included the University Hospitals of Trieste (Italy) and Innsbruck (Austria), the Central Hospital of Bolzano (Italy), and the National Cancer Institute of Aviano (CRO-Italy). The study was conducted in accordance with the Declaration of Helsinki, and it was approved by the following Ethical Committees: Ethical Committee of the Health Agency of the province of Bozen (protocol number 0081449, 01/07/2019), Ethical Committee of the Friuli-Venezia Giulia region (protocol number 20817, 02.07.2018), and the Ethical Committee of the Medical University of Innsbruck (protocol number 1177/2017 and 1182/2018). Written informed consent was obtained from all individual participants included in the study with the exception of deceased patients (permission granted by the Ethical Committee). Cases of primary CM diagnosed between 01/01/2006 and 31/12/2015 included in this study were retrieved from the histopathological databases at the corresponding participating centers. Inclusion criteria were the following: (i) Unequivocal diagnosis of primary cutaneous melanoma with a tumor thickness ≥ 1.8 mm (this thickness was chosen to provide tissue slides for molecular analyses without consuming the entire tissue block); (ii) location in the head/neck, trunk/limbs, and acral sites—trunk and head (neck and face) were chosen for men, and higher and lower limbs for women. These sites were chosen because they are mostly gender-related. Cases were matched among participant groups per gender, anatomical site, age range, and tumor thickness; and (iii) availability of the fixed-and paraffin-embedded block. The cohort included also patients with criteria (i), (ii), and (iii) of any anatomical site in patients aged ≥90 years or <30 years as extreme values of the sample. In patients with more than one primary CM, only the first CM was included while subsequent melanomas were excluded from the study.
Funding Information:
Funding: This study was supported by the project MEMS under the Grant agreement ITAT1018 as part of the EU program Interreg V-A Italia-Austria 2014−2020.
Funding Information:
Acknowledgments: The authors wish to thank Simon Schwendinger for expert help with digital droplet PCR, and Birgit Moser, Nadja Kühner and Cristina Bottin and Ermanno Nardon for excellent technical assistance. The authors would like to thank the Interreg V-A Italia-Austria 2014−2020 program which supported the project MEMS under the grant agreement ITAT1018.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
KW - Altitude
KW - Cutaneous melanoma
KW - MiRNA
KW - Molecular profiling
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U2 - 10.3390/cancers12102796
DO - 10.3390/cancers12102796
M3 - Article
VL - 12
SP - 1
EP - 23
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 10
M1 - 2796
ER -