Original Articles: Clinical researchThe prognostic role of BRAF and WNT pathways activation in kinase inhibitors-naïve clinical stage III cutaneous melanomaKowalik, Artura; Jurkowska, Monikab; Mierzejewska, Ewac; Ługowska, Iwonac,,d; Gos, Aleksandrae; Szumera-Ciećkiewicz, Annaf,,g; Zięba, Sebastiana; Koseła-Paterczyk, Hannad; van der Oord, Joosth; Dębiec-Rychter, Mariai; Szamotulska, Katarzynac; Siedlecki, Janusze; Rutkowski, PiotrdAuthor Information aDepartment of Molecular Diagnostics, Holycross Cancer Centre, Kielce bGenomed Health Care Centre cDepartment of Epidemiology and Biostatistics, Institute of Mother and Child dDepartment of Soft Tissue/Bone Sarcoma and Melanoma eDepartment of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute – Oncology Center fDiagnostic Hematology Department, Institute of Hematology and Transfusion Medicine gDepartment of Pathology and Laboratory Medicine, Maria Sklodowska-Curie Institute – Oncology Center hDepartment of Pathology, Laboratory of Translational Cell and Tissue Research iDepartment of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium Received 5 August 2019 Accepted 3 January 2020 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.melanomaresearch.com. Correspondence to Artur Kowalik, PhD, Department of Molecular Diagnostics, Holycross Cancer Center, Artwińskiego 3, 25-734 Kielce, Poland, Tel: +48 41 367 42 59; fax: +48 41 367 42 60; e-mail: [email protected] Melanoma Research: August 2020 - Volume 30 - Issue 4 - p 348-357 doi: 10.1097/CMR.0000000000000658 Buy SDC Metrics Abstract The results of local-regional advanced melanoma (stage III) management are still not satisfactory. Particularly, there is no personalized treatment in stage III melanoma patients due to the lack of useful classical pathological markers for prognostication of indolent or aggressive course of the disease. The aim of this study was to explore melanoma genomic landscape by means of the mutational profiling of 50 genes influencing carcinogenesis pathways in the randomly selected 93 kinase inhibitor-naïve (KI-naïve) stage III patients. The genomic alterations were found in 27 out of 50 tested genes and at least one pathogenic variant was detected in 77 out of 93 cases (82.7%). Survival rate was negatively affected by the presence of the somatic mutations in AKT1, ATM, CDH1 and SMARCB1, while the BRAF+ status in KI-naïve stage III population correlated with the longer median overall survival. Genomic alterations in WNT pathway correlated with extranodal adipocyte tissue involvement (P = 0.027) and higher number of metastatic lymph nodes (P = 0.045). In terms of survival, the Cox model confirmed the worse prognosis in patients with mutation in the WNT pathway [hazard ratio (HR) = 2.9, P = 0.017], and better prognosis in cases with mutations in BRAF pathway (HR = 0.5, P = 0.004). WNT/β-catenin pathway alteration was associated with more advanced/aggressive disease. From this perspective, the concept of blocking the activity of the WNT pathway in selected cases appears promising and complementary to the BRAF inhibition therapeutic option for the future. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.