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Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy‐related (ATG) genes have been investigated in relation to melanoma progression. We examined five single‐nucleotide polymorphisms (SNPs) in three ATG genes (ATG5; ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population‐based case–control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27–0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11–1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12–3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05–0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21–0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34–0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression. Autophagy is critical in cancer risk and progression, and inherited variants in autophagy genes have not been investigated in relation to melanoma. In a large population‐based study of melanoma, two SNPs were associated with stage at diagnosis and tumor infiltrating lymphocytes; one SNP was associated with thinner Breslow thickness, earlier stage at diagnosis and younger age of diagnosis. Autophagy SNPs may influence melanoma progression and should be investigated further.

BackgroundWhile checkpoint immunotherapy has revolutionized cancer treatment, responses are observed only in a subset of patients. The finite capacity of a patient’s immune system to recognize tumor mutations as foreign antigens is a major factor limiting the benefit of approved immunotherapies. Diacylglycerol kinases alpha (DGKα) and zeta (DGKζ) are expressed in T cells and play key non-redundant roles modulating the intensity of T cell receptor (TCR) signalling. Through phosphorylation of the critical secondary messenger diacylglycerol (DAG) to form phosphatidic acid, DGKs act as intracellular checkpoints attenuating T cell activation, limiting recognition of tumor antigens. DGKα cooperates with DGKζ to regulate the levels of DAG, suggesting that dual DGKα/ζ inhibition would result in the maximal biologic effect. Preclinically, inhibition of DGKα with BAY2862789 increases T cell activation and resistance to immune suppression that is further elevated in conjunction with inhibition of DGKζ by BAY2965501, to levels above either monotherapy. This suggests that BAY2862789 has the potential to strengthen patient anti-tumor responses which could be further enhanced in combination with BAY2965501.MethodsMonotherapy BAY2862789 treatment is currently under investigation in a FIH dose escalation study (NCT05858164) evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. To assess the capacity of BAY2862789 to modulate a patient’s immune responses, changes in T cell activation were tracked in peripheral blood by flow cytometry and with ex vivo assays to measure TCR downstream ERK phosphorylation and cytokine production during treatment (n≥30). A Limited number of paired biopsies were also evaluated. Additionally, to understand if BAY2862789 exposure in patients was sufficient to observe effects of DGKα/ζ dual inhibition, DGKζ inhibitor BAY2965501 was spiked into ex vivo assays to compare changes on treatment to baseline.ResultsBAY2862789 was able to achieve blood exposure above preclinically defined EC80, however, no consistent increase >2-fold from baseline was observed in ERK phosphorylation or cytokine production. Despite this, a low frequency of patients did display T cell activation in situ (>2-fold increases in Ki67+), suggesting potential pharmacologic activity. Accordingly, ex vivo assays performed on a subset of patients (n=>10), including the addition of BAY2965501, demonstrated synergistic elevation in IFNγ and IL2 production on-treatment compared to baseline.ConclusionsSpecific inhibition of DGKα by BAY2862789 alone does not lead to substantial immune modulation in patients, despite reaching sufficient exposure to synergize with BAY2965501 in ex vivo assays. Data suggests that BAY2862789 should be combined with DGKζ inhibition to achieve the greatest T cell activation in patients.

Melanoma is the most severe type of skin cancer, and the risk of developing melanoma and of dying of melanoma varies between women and men. This study investigated whether widely studied genetic single nucleotide polymorphisms (SNPs) in two oncogenes known to promote cell proliferation explain these sex differences by testing such variants in a large cohort of 3663 melanoma patients. Formal analyses demonstrated that females, but not males, who carried the variant MDM4-rs4245739*C were more likely to develop a new primary melanoma, and those with the variant MDM2-rs2279744*G were less likely to succumb to the disease. We also identified a number of additional variants, often co-inherited with the tested SNPs, which modify how these and other genes work locally in the skin, as well as in distal organs where melanoma tends to spread or invade during the progression of the disease. MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (OR[sub.per-allele] = 1.25, 95% CI 1.03-1.51, and P[sub.trend] = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HR[sub.per-allele] = 0.63, 95% CI 0.42-0.95, and P[sub.trend] = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03–1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42–0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Sex differences in melanoma are prominent, with female having a significant survival advantage. However, it is unclear why we see this survival advantage. Here, we investigate the relationship between sex, clinicopathologic variables, and melanoma specific survival in 1753 single primary melanomas from patients in the GEM (Genes, Environment, and Melanoma) study. Using Cox proportional hazard models and formal mediation analysis, the effect of sex on survival is explained largely by differences in the clinicopathologic features of tumors at diagnosis. Specifically, we find evidence that 86.5% of the effect of sex on melanoma survival is mediated by differences in age at diagnosis, Breslow thickness, ulceration, mitoses, and site (hazard ratio [HR] = 1.85, P < .001). This analysis indicates that the female survival advantage in melanoma is not primarily due to a direct effect of sex (HR = 1.19, P = .42) but is largely a result of an indirect effect of sex mediated by clinicopathologic features.

Abstract Background It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D–binding protein gene (GC), rs7041 and rs4588, determine 3 common haplotypes, Gc1s, Gc1f, and Gc2, of which Gc1f may be associated with decreased all-cause death among melanoma patients based on results of a prior study, but the association of Gc1f with melanoma-specific death is unclear. Methods We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4490 individuals with incident, invasive primary melanoma in 2 population-based studies using multivariable Cox-proportional hazards regression. Results In the pooled analysis of both datasets, the patients with the Gc1f haplotype had a 37% lower risk of melanoma-specific death than the patients without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = .001), with adjustments for age, sex, study center, first- or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those patients with the Gc1f haplotype compared with those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumor Breslow thickness equal to or less than 2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumor Breslow thickness greater than 2.0 mm (Pinteraction = .003). Conclusions Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma—specifically from thicker, higher-risk melanoma—than individuals without this Gc1f haplotype.

Everybody writes that ROC curves, a very common tool in binary classification problems, should be optimal, and in particular concave, non-decreasing and above the 45-degree line. Everybody uses ROC curves, theoretical and especially empirical, which are not so. This work is an attempt to correct this schizophrenic behavior. Optimality stems from the Neyman-Pearson lemma, which prescribes using likelihood-ratio based ROC curves. Starting from there, we give the most general definition of a likelihood-ratio based classification procedure, which encompasses finite, continuous and even more complex data types. We point out a strict relationship with a general notion of concentration of two probability measures. We give some nontrivial examples of situations with non-monotone and non-continuous likelihood ratios. Finally, we propose the ROC curve of a likelihood ratio based Gaussian kernel flexible Bayes classifier as a proper default alternative to the usual empirical ROC curve.

Introduction: Malocclusion is a pathology which has caused by multifactorial factores, being related to a lot of factors, as breastfeeding and deleterious oral habits. Objectives: The objective of this work was to verify the prevalence and association between time and type of breastfeeding with the installation of deleterious oral habits and consequential malocclusions. Materials and Methods: This is a transversal-type, observational, descriptive study, which evaluated 297 children, aged from three to five years, enrolled in municipal kindergartens. The first phase was carried out with a form directed to parents and guardians and collected information on the lactation period, presence of deleterious oral habits (DOH) and socioeconomic data. The second step consisted of the clinical occlusal examination of children whose parents or guardian had signed the Informed Consent Form and that were within the inclusion criteria of the survey. The data analysis was conducted at a level of significance of 5% through the tests χ2 and odds ratio, the OddsRatio were determined by formula OR = ad/bc, both processed in the software SPSS version 14.0.Results: Deleterious oral habits had a prevalence of 96.6% in the sample, the average time of exclusive breastfeeding was 4.57 months. The habit of highest incidence was the bottle suction, present in 69% of children, but the pacifier was the main responsible for developing malocclusions. Conclusion: The obtained data allow concluding that the breastfeeding time influenced directly the presence of deleterious oral habits and malocclusions in the primary dentition, and that digital sucking habits, pacifier sucking and baby’s bottle are associated with malocclusions in the studied population.