Association of JAK/STAT genetic variants with cutaneous melanoma

Gabriela Vilas Bôas Gomez; Gustavo Jacob Lourenço; Lummy Maria Oliveira Monteiro; Rafael Silva Rocha; Kimberly Anne McGrail Fernández; Juan Angel Recio; Caroline Torricelli; Lilian Oliveira Coser; Alexandre Leite Rodrigues Oliveira; Juliana Carron; Aparecida Machado Moraes; Carmen Silvia Passos Lima

doi:10.3389/fonc.2022.943483

Association of JAK/STAT genetic variants with cutaneous melanoma

Front Oncol. 2022 Aug 2:12:943483. doi: 10.3389/fonc.2022.943483. eCollection 2022.

Authors

Affiliations

¹ Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
² Department of Cellular and Molecular Biology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
³ Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁴ Laboratory of Nerve Regeneration, Department of Structural and Functional Biology, Institute of Biology, University of Campinas, São Paulo, Brazil.
⁵ Department of Anesthesiology, Oncology and Radiology, Faculty of Medical Sciences, University of Campinas, São Paulo, Brazil.

Abstract

Background: The Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway regulates cutaneous melanoma (CM) development and progression. The JAK1, JAK2, and STAT3 proteins are encoded by polymorphic genes. This study aimed to verify whether single-nucleotide variants (SNVs) in JAK1 (c.1648+1272G>A, c.991-27C>T), JAK2 (c.-1132G>T, c.-139G>A), and STAT3 (c.*1671T>C, c.-1937C>G) altered the risk, clinicopathological aspects, and survival of CM patients as well as protein activity.

Methods: CM patients (N = 248) and controls (N = 274) were enrolled in this study. Genotyping was performed by real-time polymerase chain reaction (PCR), and JAK1, JAK2, and STAT3 expression was assessed by quantitative PCR (qPCR). STAT3 c.-1937C>G SNV was investigated by luciferase, qPCR, western blot, apoptosis, and cell cycle assays in SKMEL-28 cells with CC or GG genotype.

Results: Individuals with STAT3 c.*1671TT and c.-1937CC genotypes and TC haplotype of both SNVs were under about 2.0-fold increased risk of CM. Specific JAK1, JAK2, and STAT3 combined genotypes were associated with up to 4.0-fold increased risk of CM. Higher luciferase activity [4,013.34 vs. 2,463.32 arbitrary units (AU); p = 0.004], STAT3 expression by qPCR (649.20 vs. 0.03 AU; p = 0.003) and western blot (1.69 vs. 1.16 AU; p = 0.01), and percentage of cells in the S phase of the cell cycle (57.54 vs. 30.73%; p = 0.04) were more frequent in SKMEL-28 with STAT3 c.-1937CC than with GG genotype. CM cell line with CC genotype presented higher STAT3 protein levels than the one with GG genotype (1.93 versus 1.27 AU, p = 0.0027).

Conclusion: Our data present preliminary evidence that inherited abnormalities in the JAK/STAT pathway can be used to identify individuals at a high risk of CM, who deserve additional attention for tumor prevention and early detection.

Keywords: JAK1; JAK2; STAT3; cutaneous melanoma; genetic variant; prognosis; risk.