Cutaneous melanoma (CM) is a low incidence tumor worldwide but is associated with high mortality. Skin exposure to ultraviolet radiation from sunlight and genetic factors are related to carcinogenesis of CM. CM is also one of the most immunogenic types of solid tumors, eliciting an active antitumor response. Regulatory T lymphocytes (Tregs) modulate the destruction of abnormal cells by binding tumor necrosis factor (TNF) to /tumor necrosis factor receptor 2 (TNFR2) on their surfaces. Treg depletion reduced the number of metastases in TNFR2-deficient animals. Basal levels of TNFR2 altered relapse-free survival in CM patients, and antibodies targeting TNFR2 on Tregs are seen as promising agents to promote tumor immune-mediated control. TNFR2 is encoded by the polymorphic gene TNFRSF1B. Therefore, the ability to destroy abnormal cells varies among individuals, and may lead to distinct risk for melanoma and distinct clinicopathological aspects in CM patients.

This study aimed to analyze the roles of TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T single nucleotide variants (SNVs) in risk of CM and in clinicopathological aspects of CM patients.

All consecutive patients with CM diagnosed at the General Hospital of the University of Campinas and the Cancer Hospital of Barretos from November 2018 to July 2000 were enrolled in study. Blood donors from the Hematology and Hemotherapy Center served as controls of the study. Clinicopathological characteristics of patients and controls were obtained from the medical records. Genotyping was performed by real-time polymerase chain reaction (RT-PCR) in DNA extracted from peripheral blood leukocytes of patients and controls. Differences between groups of patients were analyzed using Fisher's or chi-square test, and multiple comparisons were adjusted by the Bonferroni method.

A total of 433 patients and 502 controls were enrolled in the study. The TNFRSF1B c.587TT genotype was more common in patients than in controls (63.5 versus 61.6%, p = 0.04); individuals with c.587TT genotype were under 1.41 (CI95%: 1.01-1.98)-fold increased risk for CM than those with the remaining genotypes. An excess of the c.587TT genotype was seen in patients aged ≤ 54 years compared to older patients (69.5 versus 57.0%, p = 0.007). No associations of genotypes with pathological aspects of tumors were found in the study.

Our findings show, for the first time, that TNFRSF1B c.587T>G can affect the risk and age of onset of CM. Acknowledgements: The study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES #88887.337514/2019-00), Fundação de Apoio ao Ensino e à Pesquisa do Estado de São Paulo (FAPESP #2019/09168-8).