Can alterations in cathepsin levels restrain the development of skin cancer?: A bidirectional multivariate Mendelian-randomization study.

Malignant skin tumors mainly include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. There is currently observational research suggesting that changes in cathepsin (CTS) may be a factor in the development of malignant skin tumors, but no studies have yet demonstrated a causal relationship between tissue protease changes and the occurrence of malignant skin tumors. Current studies have shown that cathepsin is involved in tumor cell invasion and metastasis by regulating growth factors and cellular immune function in tumor microenvironment, decomposing extracellular matrix and basement membrane, and promoting angiogenesis. In this study, we conducted a bidirectional Mendelian-randomization study using publicly available genome-wide association study (GWAS; GWAS Catalog) data. This study applies a bidirectional multivariate Mendelian randomization (MR) approach to investigate the causal relationship between cathepsin, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. In cases where multiple cathepsins are implicated as etiological factors in certain diseases, a multivariable analysis is conducted to assess the direct and indirect causal effects of the exposure factors. In this study, we present a comprehensive MR analysis to investigate the relationship between 9 cathepsin and basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Based on our MR analysis using the largest GWAS Catalog dataset available, we are able to draw relatively reliable conclusions. In the MR study, we found that tissue protease L2 can promote skin cancer, Cathepsin O, and Cathepsin F are associated with an increased risk of basal cell carcinoma. Cathepsin H can inhibit basal cell carcinoma and malignant melanoma. In the reverse MR study, it was found that squamous cell carcinoma may cause an increase in Cathepsin O expression. In the multivariate analysis, it was found that Cathepsin H is a direct factor in reducing the occurrence of skin cancer and melanoma, with no apparent causal relationship to non-melanoma skin cancer. Cathepsin has a dual impact on skin cancer cells, and the expression of different cathepsins at the edge of skin tumors may indicate different developmental tendencies of skin cancer. Cathepsin may serve as effective biomarkers for predicting tumors.

MULTIPLE KERATINOCYTIC CANCERS AFTER INTAKE OF ANTIHYPERTENSIVES (LISINOPRIL/BISOPROLOL/HCT) AND ANTIARRHYTMICS (PROPAFENONE): THE IMPORTANT NEW LINKS TO THE NITROSO-CONTAMINATION AND THE METABOLIC REPROGRAMMING OF THE FUTURE CANCER CELL.

The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.

Non-clinical evaluation of pmIL12 gene therapy for approval of the phase I clinical study.

Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.

Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.

Micro RNA Dysregulation in Keratinocyte Carcinomas: Clinical Evidence, Functional Impact, and Future Directions.

The keratinocyte carcinomas, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs, assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment.

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. METHODS: A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. RESULTS: From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. CONCLUSION: This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.

Association between blood metabolites and basal cell carcinoma risk: a two-sample Mendelian randomization study.

Background: Circulating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC's progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression. Material and methods: We conducted a two-sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Results: In the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10-4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10-4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation. Conclusion: Our research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.

The causal relationship between immune cells mediating FIT3L, CCL4, OSM, and skin-derived deteriorated tumors.

OBJECTIVE: Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells. METHODS: This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC. RESULTS: The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p < 0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively. CONCLUSION: Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.

Causal association between skin cancer and immune cells: mendelian randomization (MR) study.

BACKGROUND: Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. METHODS: This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. RESULTS: We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. CONCLUSION: This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers.

This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.

Molecular Profiling and the Interaction of Somatic Mutations with Transcriptomic Profiles in Non-Melanoma Skin Cancer (NMSC) in a Population Exposed to Arsenic.

Exposure to inorganic arsenic (As) is recognized as a risk factor for non-melanoma skin cancer (NMSC). We followed up with 7000 adults for 6 years who were exposed to As. During follow-up, 2.2% of the males and 1.3% of the females developed basal cell carcinoma (BCC), while 0.4% of the male and 0.2% of the female participants developed squamous cell carcinoma (SCC). Using a panel of more than 400 cancer-related genes, we detected somatic mutations (SMs) in the first 32 NMSC samples (BCC = 26 and SCC = 6) by comparing paired (tissue-blood) samples from the same individual and then comparing them to the SM in healthy skin tissue from 16 participants. We identified (a) a list of NMSC-associated SMs, (b) SMs present in both NMSC and healthy skin, and (c) SMs found only in healthy skin. We also demonstrate that the presence of non-synonymous SMs in the top mutated genes (like PTCH1, NOTCH1, SYNE1, PKHD1 in BCC and TP53 in SCC) significantly affects the magnitude of differential expressions of major genes and gene pathways (basal cell carcinoma pathways, NOTCH signaling, IL-17 signaling, p53 signaling, Wnt signaling pathway). These findings may help select groups of patients for targeted therapy, like hedgehog signaling inhibitors, IL17 inhibitors, etc., in the future.

Genetic causal relationship between gut microbiota and basal cell carcinoma: A two-sample mendelian randomization study.

OBJECTIVE: Research has previously established connections between the intestinal microbiome and the progression of some cancers. However, there is a noticeable gap in the literature in regard to using Mendelian randomisation (MR) to delve into potential causal relationships between the gut microbiota (GM) and basal cell carcinoma (BCC). Therefore, the purpose of our study was to use MR to explore the causal relationship between four kinds of GM (Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae) and BCC. METHODS: We used genome-wide association study (GWAS) data and MR to explore the causal relationship between four kinds of GM and BCC. This study primarily employed the random effect inverse variance weighted (IVW) model for analysis, as complemented by additional methods including the simple mode, weighted median, weighted mode and MR‒Egger methods. We used heterogeneity and horizontal multiplicity to judge the reliability of each analysis. MR-PRESSO was mainly used to detect and correct outliers. RESULTS: The random-effects IVW results showed that Bacteroides (OR = 0.936, 95% CI = 0.787-1.113, p = 0.455), Streptococcus (OR = 0.974, 95% CI = 0.875-1.083, p = 0.629), Proteobacteria (OR = 1.113, 95% CI = 0.977-1.267, p = 0.106) and Lachnospiraceae (OR = 1.027, 95% CI = 0.899-1.173, p = 0.688) had no genetic causal relationship with BCC. All analyses revealed no horizontal pleiotropy, heterogeneity or outliers. CONCLUSION: We found that Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae do not increase the incidence of BCC at the genetic level, which provides new insight for the study of GM and BCC.

From bedside to genetic analysis: New insights into pathophysiology of melanoma, basal cell carcinoma, and other cancers.

OBJECTIVE: Patients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non-sun exposed skin. Simultaneously a large study published in the Journal of American Medical Association (JAMA) illustrated that patients with MMD have "overall" an increased risk for cancer development. Based on these findings, this author in 2010 postulated that dysregulation of RNA binding proteins (RBP), responsible for clinical manifestations of MMD, is also responsible for the development of BCC and melanoma. METHODS: To report new research elucidating the etiology of melanoma, BCC, MMD-induced cancers, and potentially other environmentally induced malignancies. RESULTS: Dysregulation of RBP induces aberrant mRNA splicing; recent data indicates that abnormal mRNA splicing not just plays a key role in the pathogenesis of melanoma but is a hallmark of essentially all human malignancies. CONCLUSION: The author's hypothesis is that ultraviolet (UV) radiation induces DNA damage in intronic regions of a variety of genes. Furthermore, these UV-induced abnormal DNA dimers, repeats and mutations interfere with normal mRNA splicing thus producing abnormal proteins. These abnormal proteins in turn activate oncogenic pathways such as hedgehog, MAP kinase, and WNT.

Genetically predicted TWEAK mediates the association between lipidome and Keratinocyte Carcinomas.

BACKGROUND: Reports suggest that lipid profiles may be linked to the likelihood of developing skin cancer, yet the exact causal relationship is still unknown. OBJECTIVE: This study aimed to examine the connection between lipidome and skin cancers, as well as investigate any possible mediators. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted on 179 lipidomes and each skin cancer based on a genome-wide association study (GWAS), including melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Then, Bayesian weighted MR was performed to verify the analysis results of two-sample MR. Moreover, a two-step MR was employed to investigate the impact of TNF-like weak inducer of apoptosis (TWEAK)-mediated lipidome on skin cancer rates. RESULTS: MR analysis identified higher genetically predicted phosphatidylcholine (PC) (17:0_18:2) could reduce the risk of skin tumors, including BCC (OR = 0.9149, 95% CI: 0.8667-0.9658), SCC (OR = 0.9343, 95% CI: 0.9087-0.9606) and melanoma (OR = 0.9982, 95% CI: 0.9966-0.9997). The proportion of PC (17:0_18:2) predicted by TWEAK-mediated genetic prediction was 6.6 % in BCC and 7.6% in SCC. The causal relationship between PC (17:0_18:2) and melanoma was not mediated by TWEAK. CONCLUSION: This study identified a negative causal relationship between PC (17:0_18:2) and keratinocyte carcinomas, a small part of which was mediated by TWEAK, and most of the remaining mediating factors are still unclear. Further research on other risk factors is needed in the future.

Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

Causal relationship between genetically determined plasma metabolites and skin cancer: a two-sample Mendelian randomization study.

We aimed to unveil the underlying pathogenic mechanisms of skin cancer in relation to metabolic factors and pathway mechanisms. This study utilized the TwoSample Mendelian randomization (MR) method to investigate the causal relationship between 1400 plasma metabolites and skin cancer. The primary method employed was the inverse variance weighting (IVW). Through IVW analysis, we found 105 plasma metabolites associated with Basal Cell Carcinoma (BCC), with the highest association observed for Prolylglycine levels (OR [95% CI]: 1.1902 [1.0274, 1.3788]). For Malignant Melanoma of Skin (MSS), 68 plasma metabolites were linked, with the highest causal relationship seen for 3-Hydroxybutyrate levels (OR [95% CI]: 1.0030 [1.0013, 1.0048]). Regarding actinic keratosis (AK), and the highest association observed for Hexadecadienoate (16:2n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.7125]). Glycerol to palmitoylcarnitine (16: n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.125]) were found to be significant for BCC and AK. Palmitoylcarnitine (C16) had the most positive causal effect for BCC (OR [95% CI]: 1.1777 [1.0493, 1.3218]), while 5-hydroxy-2-methylpyridine sulfate levels had the highest effect for AK (OR [95% CI]: 1.1788 [1.0295, 1.3498]). And 4-guanidinobutanoate levels had the largest positive causal effect (OR [95% CI]: 1.0857 [1.0417, 1.1317]) for BCC, and X-11880 levels for MSS (OR [95% CI]: 1.0013 [1.0000, 1.0025]). The study revealed a positive association between hereditary Glycerol to palmitoylcarnitine (C16) and 5-hydroxy-2-methylpyridine sulfate levels with the risk of developing BCC and AK. Additionally, 4-guanidinobutanoate levels and X 11880 levels were found to be positively associated with the risk of BCC and MMS.

Genetic predisposition to childhood obesity does not influence the risk of developing skin cancer in adulthood.

The relationship between body mass index (BMI) and melanoma and other skin cancers remains unclear. The objective of this study was to employ the Mendelian randomization (MR) approach to evaluate the effects of genetically predicted childhood adiposity on the risk of developing skin cancer later in life. Two-sample MR analyses were conducted using summary data from genome-wide association study (GWAS) meta-analyses of childhood BMI, melanoma, cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). We used the inverse-variance-weighted (IVW) methods to obtain a pooled estimate across all genetic variants for childhood BMI. We performed multiple sensitivity analyses to evaluate the potential influence of various assumptions on our findings. We found no evidence that genetically predicted childhood BMI was associated with risks of developing melanoma, cSCC, or BCC in adulthood (OR, 95% CI: melanoma: 1.02 (0.93-1.13), cSCC 0.94 (0.79-1.11), BCC 0.97 (0.84-1.12)). Our findings do not support the conclusions from observational studies that childhood BMI is associated with increased risks of melanoma, cSCC, or BCC in adulthood. Intervening on childhood adiposity will not reduce the risk of common skin cancers later in life.

Investigation of Genetic Association Between a High Activity Variant of Cathepsin G and Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: Cathepsin G (CTSG) has been identified as an inhibitor of breast, bladder, and colorectal cancers. The G allele of the N125S (A/G, rs45567233) functional polymorphism of the CTSG gene confers increased serum CTSG activity and has been associated with cardiovascular and neurovascular diseases. This study examined the possible correlation between the pathogenesis of basal cell carcinoma (BCC) and the functional polymorphism CTSG N125S. PATIENTS AND METHODS: A total of 197 DNA samples were examined, comprising 98 BCC patients and 99 control samples of Greek origin. The CTSG N125S polymorphism was molecularly genotyped using PCR amplification, followed by enzyme digestion, and agarose gel electrophoresis of the amplified DNA fragments. RESULTS: There was no statistically significant difference in the genotypic and allelic frequencies between the patient and the control groups. CONCLUSION: There is no association between the CTSG N125S polymorphism and pathogenesis of BCC.