Gender Disparity and Mutation Burden in Metastatic Melanoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Gupta S
PROVIDER: S-EPMC4643631 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
Gender Disparity and Mutation Burden in Metastatic Melanoma.
Gupta Sameer S Artomov Mykyta M Goggins William W Daly Mark M Tsao Hensin H
Journal of the National Cancer Institute 20150820 11
Gender differences in melanoma incidence and outcome have been consistently observed but remain biologically unexplained. We hypothesized that tumors are genetically distinct between men and women and analyzed the mutation spectra in 266 metastatic melanomas (102 women and 164 men) from The Cancer Genome Atlas (TCGA). We found a statistically significantly greater burden of missense mutations among men (male median 298 vs female median = 211.5; male-to-female ratio [M:F] = 1.85, 95% confidence i ...[more]
Similar Datasets
Project description:BackgroundTo evaluate the global burden of cataracts by year, age, region, gender, and socioeconomic status using disability-adjusted life years (DALYs) and prevalence from the Global Burden of Disease (GBD) study 2019.MethodsGlobal, regional, or national DALY numbers, crude DALY rates, and age-standardized DALY rates caused by cataracts, by year, age, and gender, were obtained from the Global Burden of Disease Study 2019. Socio-demographic Index (SDI) as a comprehensive indicator of the national or regional development status of GBD countries in 2019 was obtained from the GBD official website. Kruskal-Wallis test, linear regression, and Pearson correlation analysis were performed to explore the associations between the health burden with socioeconomic levels, Wilcoxon Signed-Rank Test was used to investigate the gender disparity.ResultsFrom 1990 to 2019, global DALY numbers caused by cataracts rose by 91.2%, crude rates increased by 32.2%, while age-standardized rates fell by 11.0%. Globally, age-standardized prevalence and DALYs rates of cataracts peaked in 2017 and 2000, with the prevalence rate of 1283.53 [95% uncertainty interval (UI) 1134.46-1442.93] and DALYs rate of 94.52 (95% UI 67.09-127.24) per 100,000 population, respectively. The burden was expected to decrease to 1232.33 (95% UI 942.33-1522.33) and 91.52 (95% UI 87.11-95.94) by 2050. Southeast Asia had the highest blindness rate caused by cataracts in terms of age-standardized DALY rates (99.87, 95% UI: 67.18-144.25) in 2019. Gender disparity has existed since 1990, with the female being more heavily impacted. This pattern remained with aging among different stages of vision impairments and varied through GBD super regions. Gender difference (females minus males) of age-standardized DALYs (equation: Y = -53.2*X + 50.0, P < 0.001) and prevalence rates (equation: Y = - 492.8*X + 521.6, P < 0.001) was negatively correlated with SDI in linear regression.ConclusionThe global health of cataracts is improving but the steady growth in crude DALY rates suggested that health progress does not mean fewer demands for cataracts. Globally, older age, females, and lower socioeconomic status are associated with higher cataract burden. The findings of this study highlight the importance to make gender-sensitive health policies to manage global vision loss caused by cataracts, especially in low SDI regions.
| S-EPMC9652134 | biostudies-literature
Project description:The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.
| S-EPMC4945874 | biostudies-literature
Project description:The genesis of hepatocellular carcinoma (HCC) is closely related to hyper-activated Ras signals and male factors. This study aimed to characterize the underlying mechanisms by examining the transcriptome of Hras12V transgenic mice (Ras-Tg, HCC model). A transcriptomic database was established via RNA-Seq of HCC (T) and the adjacent precancerous liver tissue (P) of Ras-Tg and the normal liver tissue of wild-type mice (W) of both sexes. Bioinformatics analysis as well as metabolite and gene expression assays were performed. Totally, 2708 differentially expressed genes (DEGs) were screened out (FC ≥ 2 and q < 0.05). Longitudinal comparative analysis within W, P, and T and correlation expression pattern analysis revealed common/unique cluster-enriched items towards HCC between the sexes. Specifically, the numbers of DEGs were much higher in females than in males, and tumor suppressor genes, such as p21Waf1/Cip1 and C6, were significantly higher in the female P. This finding denotes the higher sensitivity of female hepatocytes to the Ras oncogene and, therefore, the difficulty in developing HCC. Moreover, convergence in HCC between the sexes suggests the underlying mechanisms for ineffectiveness of sex hormone therapies. Additionally, expression pattern analysis revealed that the DEGs and their relevant pathways were either positively or negatively associated with the HCC/Ras oncogene. Among them, the vital role of glutathione metabolism in HCC was established. The systemic transcriptomic database of the Ras oncogene-induced HCC with sex disparities provides valuable clues for elucidating the underlying mechanisms, selecting the diagnostic biomarker, and planning the clinical therapy in HCC.
2024-05-18 | GSE232694 | GEO
Project description:Melanoma tumors are the most heterogeneous of all tumor types. Tumor heterogeneity results in difficulties in diagnosis and is a frequent cause of failure in treatment. Novel techniques enable accurate examination of the tumor cells, considering their heterogeneity. The study aimed to determine the somatic variations among high and low proliferating compartments of melanoma tumors. In this study, 12 archival formalin-fixed paraffin-embedded samples of previously untreated primary cutaneous melanoma were stained with Ki-67 antibody. High and low proliferating compartments from four melanoma tumors were dissected using laser-capture microdissection. DNA was isolated and analyzed quantitatively and qualitatively. Libraries for amplicon-based next-generation sequencing (NGS) were prepared using NEBNext Direct Cancer HotSpot Panel. NGS detected 206 variants in 42 genes in melanoma samples. Most of them were located within exons (135, 66%) and were predominantly non-synonymous single nucleotide variants (99, 73.3%). The analysis showed significant differences in mutational profiles between high and low proliferation compartments of melanoma tumors. Moreover, a significantly higher percentage of variants were detected only in high proliferation compartments (39%) compared to low proliferation regions (16%, p < 0.05). Our results suggest a significant functional role of genetic heterogeneity in melanoma.
| S-EPMC8069012 | biostudies-literature
Project description:BackgroundInformation on costs of managing adverse events (AEs) associated with current treatments in metastatic melanoma is limited. This study estimates costs of AEs in eight countries: Australia (AU), Canada (CA), France (FR), Germany (GE), Italy (IT), the Netherlands (NL), Spain (ES), and the UK.MethodsA literature search was conducted to identify grade 3/4 AEs from product label, published trials, conference abstracts, and treatment guidelines. Resource utilization for the management of each type of AE was determined via interviews with 5 melanoma clinicians in each country. Outpatient and inpatient costs were estimated for each type of AE using country-specific tariffs or government/published sources.ResultsIn outpatient settings, the most costly AEs per incident included cutaneous squamous cell carcinoma (CSCC) (€1063, £720; NL/UK), anemia (€1443, €1329, €1285; ES/IT/FR), peripheral neuropathy (€1289; ES), and immune-related diarrhea (AUS$1,121; AU). In inpatient settings, the most costly AEs per hospitalization included hypophysitis (€10,265; €5316; CAN$9735; AUS$7231: ES/FR/CA/AU), dyspnea (€9077; GE), elevated liver enzymes (€6913, CAN$8030, AUS$6594; FR/CA/AU), CSCC (CAN$8934; CA), peripheral neuropathy (€6977, €4144, CAN$9472; NL/ES/CA), and diarrhea (£4284, €4113; UK/ES).ConclusionsCosts of managing AEs can be significant, and thus effective treatments with lower rates of severe AEs would be valuable.
| S-EPMC5209401 | biostudies-literature
Project description:Importance:It is necessary to understand the mechanisms of metastasis of uveal melanoma to advise patients and develop treatments for this tumor. Objective:To examine the stochastic properties of primary uveal melanoma including the mutation rate as a function of tumor size and metastatic rate relative to the type of mutation. Design, Setting, and Participants:We computed the mutation rate in different sized uveal melanomas using previously published large data sets. Tumor volume was estimated using the spherical cap method. We also calculated the metastatic rate using an updated data set of patients with uveal melanoma with known mutations in BAP1, SF3B1, and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group. Data were analyzed from 2 studies, one taking place from August 25, 1970, to August 27, 2008, and the other taking place between 1993 and 2013. Data were analyzed between 2016 and 2017. Main Outcomes and Measures:Mutation rates and metastic rates. Results:Based on the 5-year metastatic rates, mutation rates ranged from 1.09 × 10-8 to 7.86 × 10-7 per cell division, using our calculation algorithm. A higher mutation rate was found for tumors with smaller thicknesses. EIF1AX mutations were not exclusive of other mutations because 2 cases with EIF1AX mutations and metastasis also had BAP1 mutations. None of the tumors with only an EIF1AX mutation metastasized. After plotting the yearly metastatic rate vs time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations. Conclusions and Relevance:We observed a higher mutation rate for smaller tumors, which may be explained by a greater number of cell divisions occurring during the expansion phase of smaller uveal melanomas. Regarding time to clinically detected metastases, the first 2 peaks appear to be associated with BAP1-mutated tumors and the late peak to SF3B1-mutated tumors.
| S-EPMC6233840 | biostudies-literature
Project description:BackgroundWomen surgeons face numerous barriers to career advancement. Inequitable citation of surgical literature may represent a contributing factor to gender disparities in academic surgery.Study designThis was a cross-sectional analysis of publications from 50 top-ranking surgery journals in 2017 and 2018, as defined by the 2019 InCites Journal Citation Reports. The citation rate of publications by women vs men first authors was compared. Similarly, the citation rate of publications by men vs women last authors was also compared. Adjusted regression analyses of citation rates accounted for the time interval since publication as well as the journal within which the article was published, among other potential confounding factors.ResultsA total of 19,084 publications from 48 surgery journals with a median (interquartile range) of 8 (4 to 15) citations contributing to a median (interquartile range) Journal Impact Factor of 4.0 (3.4 to 4.6) were analyzed. Compared with man-first author publications, woman-first author publications demonstrated a 9% lower citation rate (incidence rate ratio 0.91, p < 0.001). Similarly, compared with publications by man-last authors, woman-last author publications demonstrated a 4% lower citation rate (incidence rate ratio 0.96, p = 0.03). These associations persisted after multivariable adjustment for additional confounding factors, however, not on sensitivity analysis of 24 of the highest-ranking journals.ConclusionsAmong top-tier surgical journals, publications by women-first and -last authors were less cited compared with publications by men-first and -last authors, but not among the highest-tier surgical journals. Gender bias may exist in the citation of surgical research, contributing to gender disparities in academic surgery.
| S-EPMC8931844 | biostudies-literature
Project description:BackgroundCirculating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB).MethodsThirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).ResultsCtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.ConclusionsWe showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.
| S-EPMC6038195 | biostudies-literature
Project description:BackgroundImmunotherapy is a vital component in cancer treatment. However, due to the complex genetic bases of cancer, a clear prediction index for efficacy has not been established. Tumor mutation burden (TMB) is one of the essential factors that affect immunotherapeutic efficacies, but it has not been determined whether the mutation is associated with the survival of Skin Cutaneous Melanoma (SKCM) patients. This study aimed at evaluating the correlation between TMB and immune infiltration.MethodsSomatic mutation profiles (n = 467), transcriptome data (n = 471), and their clinical information (n = 447) of all SKCM samples were downloaded from The Cancer Genome Atlas (TCGA) database. For each sample, TMB was calculated as the number of variants per megabase. Based on K-M survival analysis, they were allocated into the high-TMB and low-TMB groups (the optimal cutoff was determined by the 'surv_cutpoint' algorithm of survival R package). Then, Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) were performed, with immune-associated biological pathways found to be significantly enriched in the low-TMB group. Therefore, immune genes that were differentially expressed between the two groups were evaluated in Cox regression to determine their prognostic values, and a four-gene TMB immune prognostic model (TMB-IP) was constructed.ResultsElevated TMB levels were associated with better survival outcomes in SKCM patients. Based on the cutoff value in OS analysis, they were divided into high-TMB and low-TMB groups. GSEA revealed that the low-TMB group was associated with immunity while intersection analysis revealed that there were 38 differentially expressed immune-related genes between the two groups. Four TMB-associated immune genes were used to construct a TMB-IP model. The AUC of the ROC curve of this model reached a maximum of 0.75 (95%CI, 0.66-0.85) for OS outcomes. Validation in each clinical subgroup confirmed the efficacy of the model to distinguish between high and low TMB-IP score patients.ConclusionsIn SKCM patients, low TMB was associated with worse survival outcomes and enriched immune-associated pathways. The four TMB-associated immune genes model can effectively distinguish between high and low-risk patients.
| S-EPMC8034108 | biostudies-literature
Project description:Background: Melanoma is highly immunogenic and therefore suitable for immunotherapy, but the efficacy is limited by response rate. In several types of tumor, tumor mutation burden (TMB) and immune infiltration have been reported to predict the response to immunotherapy, although each has its limitations. In the current study, we aimed to explore the association of TMB with immune infiltration and prognosis in cutaneous melanoma. Methods: The data of cutaneous melanoma used for analyses was downloaded from The Cancer Genome Atlas (TCGA) database. The mutation data was sorted using "maftools" R package. TMB was estimated and then patients were divided into two groups based on TMB. The association of TMB with prognosis and clinical characteristics was explored. Differential analysis between two TMB groups was performed using "DESeq2" R package to identify differentially expressed genes (DEGs). The function enrichment analyses of DEGs were conducted to screen critical pathways. Besides, DEGs were further filtered to identify two hub genes, based on which a risk score model and nomogram for predicting prognosis were conducted, and the validation was performed using three datasets from Gene Expression Omnibus (GEO) database. Finally, CIBERSORT algorithm and TIMER database were used to assess the effect of TMB and hub genes on immune infiltration. Results: The most common mutation was C > T, and the top three frequently mutated genes were TTN, MUC16, and BRAF. Higher TMB indicated better survival outcomes and lower pathological stages. 735 DEGs were identified and mainly involved in immune-related and adhesion-related pathways. The risk score model and nomogram were validated using receiver operating characteristic (ROC) curves and calibration curves, and exhibited relatively high predictive capability. Decision curve analysis (DCA) was used to assess clinical benefit. As for immune infiltration, the proportion was higher for macrophages M1 and M2 in the high-TMB group, while lower for memory B cells and regulatory T cells. Conclusions: In cutaneous melanoma, TMB was positively correlated with prognosis. The risk score model and nomogram can be conveniently used to predict prognosis. The association of TMB with immune infiltration can help improve the predicting methods for the response to immunotherapy.
| S-EPMC7531222 | biostudies-literature