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Background: Epidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work. Methods: A genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran's Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes. Results: The two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p=0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism (p>0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis. Conclusion: Although themagnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate angiopoietin-2 (Ang-2/ ANGPT2) expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma (CMM). Methods: Gene expression differences between metastatic melanoma and melanoma in situ in 472 patients from the TCGA database were analyzed. The target gene Ang-2 was screened. A clinical study was conducted to analyze the correlation between Ang-2 expression in CMM and tumor-associated lymphangiogenesis. A total of 42 patients with primary CMM who underwent extended tumor resection procedures at the Affiliated Hospital of Jiangsu University were included in this study. Clinical data (gender, age, lymph node metastasis, Breslow thickness, and clinical stage) were collected. The expression levels of both Ang-2 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) proteins were detected by immunohistochemistry (IHC). Lymphatic vascular density (LVD) was counted by using LYVE-1 to label lymphatic endothelial cells (LECs) in peritumoral and intratumoral areas per highmagnification field of view. Statistical analysis was performed using the Pearson correlation test and Student's t-test. Results: Using the TCGA database, it was found that the gene expression level of Ang-2 in 368 cases of metastatic melanoma was significantly higher than that in 104 cases of melanoma in situ. Correlation analysis showed a significant relationship between Ang-2 and LYVE-1, and vascular endothelial growth factor receptor 3(VEGFR3) expression, respectively, in CMM. Moreover, the optimal cutoff value of survival analysis showed that high Ang-2 expression in CMM had a worse prognosis, based on data from the TCGA database. Our research showed that Ang-2 was more highly expressed in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients than in the group of patients with no lymph node metastasis and in the group of stage 0-3B patients. Our research also showed that LVD in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients was significantly higher than that in the group of no lymph node metastasis and in the group of stage 0-3B patients, respectively. Breslow thickness also correlated with Ang-2 expression and LVD. Ang-2 expression was not related to sex or age. Ang-2 expression was obviously correlated with LVD. Conclusion: An evaluation of Ang-2 expression and LVD can be used to predict the risk of tumor lymphatic metastasis and determine the prognosis of CMM. These results may also provide a new clinical treatment strategy for CMM. [ABSTRACT FROM AUTHOR]

Current public health advice is that high ultraviolet radiation (UVR) exposure is the primary cause of Malignant Melanoma of skin (CMM), however, despite the use of sun-blocking products incidence of melanoma is increasing. To investigate the UVR influence on CMM incidence worldwide WHO, United Nations, World Bank databases and literature provided 182 country-specific melanoma incidence estimates, daily UVR levels, skin colour (EEL), socioeconomic status (GDP PPP), magnitude of reduced natural selection (Ibs), ageing, urbanization, percentage of European descendants (Eu%), and depigmentation (blonde hair colour), for parametric and non-parametric correlations, multivariate regressions and analyses of variance. Worldwide, UVR levels showed negative correlation with melanoma incidence (“rho” = −0.515, p < 0.001), remaining significant and negative in parametric partial correlation (r = −0.513, p < 0.001) with other variables kept constant. After standardising melanoma incidence for Eu%, melanoma correlation with UVR disappeared completely (“rho” = 0.004, p = 0.967, n = 127). The results question classical views that UVR causes melanoma. No correlation between UVR level and melanoma incidence was present when Eu% (depigmented or light skin type) was kept statistically constant, even after adjusting for other known variables. Countries with lower UVR levels and more Eu% (depigmented or light skin people) have higher melanoma incidence. Critically, this means that individual genetic low skin pigmentation factors predict melanoma risk regardless of UVR exposure levels, and even at low-UVR levels.

Purpose: Cutaneous malignant melanoma (CMM) always presents as a complex disease process with poor prognosis. The objective of the present study was to explore the influence of solitary or multiple cancers on the prognosis of patients with CMM to better understand the landscape of CMM. Methods: We reviewed the records of CMM patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results Program. The cumulative incidence function was used to represent the probabilities of death. A novel causal inference method was leveraged to explore the risk difference to death between different types of CMM, and nomograms were built based on competing risk models. Results: The analysis cohort contained 165,043 patients with CMM as the first primary malignancy. Patients with recurrent CMM and multiple primary tumors had similar overall survival status (p = 0.064), while their demographics and cause-specific death demonstrated different characteristics than those of patients with solitary CMM (p < 0.001), whose mean survival times are 75.4 and 77.3 months and 66.2 months, respectively. Causal inference was further applied to unveil the risk difference of solitary and multiple tumors in subgroups, which was significantly different from the total population (p < 0.05), and vulnerable groups with high risk of death were identified. The established competing risk nomograms had a concordance index >0.6 on predicting the probabilities of death of CMM or other cancers individually across types of CMM. Conclusion: Patients with different types of CMM had different prognostic characteristics and different risk of cause-specific death. The results of this study are of great significance in identifying the high risk of cause-specific death, enabling targeted intervention in the early period at both the population and individual levels. [ABSTRACT FROM AUTHOR]

PurposeCutaneous malignant melanoma (CMM) always presents as a complex disease process with poor prognosis. The objective of the present study was to explore the influence of solitary or multiple cancers on the prognosis of patients with CMM to better understand the landscape of CMM.MethodsWe reviewed the records of CMM patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results Program. The cumulative incidence function was used to represent the probabilities of death. A novel causal inference method was leveraged to explore the risk difference to death between different types of CMM, and nomograms were built based on competing risk models.ResultsThe analysis cohort contained 165,043 patients with CMM as the first primary malignancy. Patients with recurrent CMM and multiple primary tumors had similar overall survival status (p = 0.064), while their demographics and cause-specific death demonstrated different characteristics than those of patients with solitary CMM (p < 0.001), whose mean survival times are 75.4 and 77.3 months and 66.2 months, respectively. Causal inference was further applied to unveil the risk difference of solitary and multiple tumors in subgroups, which was significantly different from the total population (p < 0.05), and vulnerable groups with high risk of death were identified. The established competing risk nomograms had a concordance index >0.6 on predicting the probabilities of death of CMM or other cancers individually across types of CMM.ConclusionPatients with different types of CMM had different prognostic characteristics and different risk of cause-specific death. The results of this study are of great significance in identifying the high risk of cause-specific death, enabling targeted intervention in the early period at both the population and individual levels.

Background: Epidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work., Methods: A genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran's Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes., Results: The two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p =0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism ( p >0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis., Conclusion: Although the magnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dong, Pan, Shen, Xu, Hu, Hu and Fei.)

Objective: The aim of this study was to investigate angiopoietin-2 (Ang-2/ANGPT2) expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma (CMM)., Methods: Gene expression differences between metastatic melanoma and melanoma in situ in 472 patients from the TCGA database were analyzed. The target gene Ang-2 was screened. A clinical study was conducted to analyze the correlation between Ang-2 expression in CMM and tumor-associated lymphangiogenesis. A total of 42 patients with primary CMM who underwent extended tumor resection procedures at the Affiliated Hospital of Jiangsu University were included in this study. Clinical data (gender, age, lymph node metastasis, Breslow thickness, and clinical stage) were collected. The expression levels of both Ang-2 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) proteins were detected by immunohistochemistry (IHC). Lymphatic vascular density (LVD) was counted by using LYVE-1 to label lymphatic endothelial cells (LECs) in peritumoral and intratumoral areas per high-magnification field of view. Statistical analysis was performed using the Pearson correlation test and Student's t -test., Results: Using the TCGA database, it was found that the gene expression level of Ang-2 in 368 cases of metastatic melanoma was significantly higher than that in 104 cases of melanoma in situ . Correlation analysis showed a significant relationship between Ang-2 and LYVE-1, and vascular endothelial growth factor receptor 3(VEGFR3) expression, respectively, in CMM. Moreover, the optimal cutoff value of survival analysis showed that high Ang-2 expression in CMM had a worse prognosis, based on data from the TCGA database. Our research showed that Ang-2 was more highly expressed in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients than in the group of patients with no lymph node metastasis and in the group of stage 0-3B patients. Our research also showed that LVD in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients was significantly higher than that in the group of no lymph node metastasis and in the group of stage 0-3B patients, respectively. Breslow thickness also correlated with Ang-2 expression and LVD. Ang-2 expression was not related to sex or age. Ang-2 expression was obviously correlated with LVD., Conclusion: An evaluation of Ang-2 expression and LVD can be used to predict the risk of tumor lymphatic metastasis and determine the prognosis of CMM. These results may also provide a new clinical treatment strategy for CMM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Ju, Yang and Yan.)

Current public health advice is that high ultraviolet radiation (UVR) exposure is the primary cause of Malignant Melanoma of skin (CMM), however, despite the use of sun-blocking products incidence of melanoma is increasing. To investigate the UVR influence on CMM incidence worldwide WHO, United Nations, World Bank databases and literature provided 182 country-specific melanoma incidence estimates, daily UVR levels, skin colour (EEL), socioeconomic status (GDP PPP), magnitude of reduced natural selection (Ibs), ageing, urbanization, percentage of European descendants (Eu%), and depigmentation (blonde hair colour), for parametric and non-parametric correlations, multivariate regressions and analyses of variance. Worldwide, UVR levels showed negative correlation with melanoma incidence ("rho" = -0.515, p < 0.001), remaining significant and negative in parametric partial correlation (r = -0.513, p < 0.001) with other variables kept constant. After standardising melanoma incidence for Eu%, melanoma correlation with UVR disappeared completely ("rho" = 0.004, p = 0.967, n = 127). The results question classical views that UVR causes melanoma. No correlation between UVR level and melanoma incidence was present when Eu% (depigmented or light skin type) was kept statistically constant, even after adjusting for other known variables. Countries with lower UVR levels and more Eu% (depigmented or light skin people) have higher melanoma incidence. Critically, this means that individual genetic low skin pigmentation factors predict melanoma risk regardless of UVR exposure levels, and even at low-UVR levels., Competing Interests: Conflict of interest: The authors have no competing interests to declare., (© 2022 the Author(s), licensee AIMS Press.)