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

TITLE=Association of JAK/STAT genetic variants with cutaneous melanoma

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.943483

DOI=10.3389/fonc.2022.943483

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>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 <italic>JAK1</italic> (c.1648+1272G&gt;A, c.991-27C&gt;T), <italic>JAK2</italic> (c.-1132G&gt;T, c.-139G&gt;A), and <italic>STAT3</italic> (c.*1671T&gt;C, c.-1937C&gt;G) altered the risk, clinicopathological aspects, and survival of CM patients as well as protein activity.</p></sec><sec><title>Methods</title><p>CM patients (<italic>N</italic> = 248) and controls (<italic>N</italic> = 274) were enrolled in this study. Genotyping was performed by real-time polymerase chain reaction (PCR), and <italic>JAK1</italic>, <italic>JAK2</italic>, and <italic>STAT3</italic> expression was assessed by quantitative PCR (qPCR). <italic>STAT3</italic> c.-1937C&gt;G SNV was investigated by luciferase, qPCR, western blot, apoptosis, and cell cycle assays in SKMEL-28 cells with CC or GG genotype.</p></sec><sec><title>Results</title><p>Individuals with <italic>STAT3</italic> c.*1671TT and c.-1937CC genotypes and TC haplotype of both SNVs were under about 2.0-fold increased risk of CM. Specific <italic>JAK1</italic>, <italic>JAK2</italic>, and <italic>STAT3</italic> 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); <italic>p</italic> = 0.004], <italic>STAT3</italic> expression by qPCR (649.20 <italic>vs</italic>. 0.03 AU; <italic>p</italic> = 0.003) and western blot (1.69 <italic>vs</italic>. 1.16 AU; <italic>p</italic> = 0.01), and percentage of cells in the S phase of the cell cycle (57.54 vs. 30.73%; <italic>p</italic> = 0.04) were more frequent in SKMEL-28 with <italic>STAT3</italic> 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 <italic>versus</italic> 1.27 AU, <italic>p</italic> = 0.0027).</p></sec><sec><title>Conclusion</title><p>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.</p></sec>