Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients.
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SUBMITTER: Pflugfelder A
PROVIDER: S-EPMC9139953 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Genome-Wide Association Study Suggests the Variant rs7551288*A within the <i>DHCR24</i> Gene Is Associated with Poor Overall Survival in Melanoma Patients.
Pflugfelder Annette A Yong Xuan Ling Hilary XLH Jagirdar Kasturee K Eigentler Thomas K TK Soyer H Peter HP Sturm Richard A RA Flatz Lukas L Duffy David L DL
Cancers 20220513 10
Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed ...[more]
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Project description:Importance:Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction. Objective:To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma. Design, Setting, and Participants:This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed. Main Outcomes and Measures:Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age. Results:A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P = .04) and overall survival (not reached vs 10.1 months; P = .009) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts. Conclusions and Relevance:Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.
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Project description:ImportanceAlthough previous database studies suggest that Mohs micrographic surgery (MMS) treatment is associated with improved overall survival (OS) for head and neck melanomas, outcomes for trunk and extremity (T&E) tumors have not been adequately evaluated.ObjectiveTo assess survival outcomes for patients with melanomas of the T&E treated with MMS vs wide local excision (WLE).Design, setting, and participantsThis retrospective cohort study examined deidentified data from the National Cancer Database between 2004 and 2015. Inclusion criteria for the analysis included diagnosis of trunk, upper extremity, or lower extremity melanoma; known Breslow depth; removal by MMS or WLE; and known last date of survival status.Main outcomes and measuresFive-year all-cause mortality (ACM) rates.ResultsA total of 188 862 in situ and invasive melanomas were included in the analysis (MMS, 2.3%; WLE, 97.7%); the mean (SD) age of patients included was 58.8 (16.0) years, and 52.7% were male. Multivariate analysis demonstrated no OS difference among trunk (WLE hazard ratio [HR], 1.097; 95% CI, 0.950-1.267; P = .21), upper extremity (WLE HR, 1.013; 95% CI, 0.872-1.176; P = .87), lower extremity (WLE HR, 0.934; 95% CI, 0.770-1.134; P = .49), or combined T&E (WLE HR, 1.031; 95% CI, 0.941-1.130; P = .51) tumors. Factors associated with increased risk of ACM on multivariate analysis of all tumors included increasing age (HR, 1.043; 95% CI, 1.042-1.044; P < .001), no insurance or nonprivate insurance (none: HR, 1.921 [95% CI, 1.782-2.071]; Medicaid: HR, 2.410 [95% CI, 2.242-2.591]; Medicare: HR, 1.237 [95% CI, 1.194-1.281]; other government insurance: HR, 1.279 [95% CI, 1.117-1.465]; P < .001 for all), positive surgical margins (HR, 1.609; 95% CI, 1.512-1.712; P < .001), a Charlson-Deyo comorbidity score greater than 0 (Charlson-Deyo score of 1: HR, 1.340; 95% CI, 1.295-1.385; P < .001; Charlson-Deyo score of ≥2: HR, 2.044; 95% CI, 1.934-2.159; P < .001), tumor ulceration (HR, 2.175; 95% CI, 2.114-2.238; P < .001), and increasing Breslow depth (HR, 1.002 [per 0.1 mm]; P < .001). Female sex (HR, 0.698; 95% CI, 0.680-0.716; P < .001) and nonnodular subtype (lentigo maligna/lentigo maligna melanoma: HR, 0.743; 95% CI, 0.686-0.805; P < .001; superficial spreading: HR, 0.739; 95% CI, 0.710-0.769; P < .001; other subtype: HR, 0.817; 95% CI, 0.790-0.845; P < .001; nodular: HR, 1 [reference]) were associated with improved OS.Conclusions and relevanceThis cohort study of patients surgically treated for melanomas of the trunk and/or extremities found that, compared with WLE, MMS was not associated with significantly different OS for T&E melanomas.
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Project description:BackgroundGlioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival.MethodsWe used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes.ResultsFifty-seven GBM patients (mean age, 57.8 ± 13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates.ConclusionsThese findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning.
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Project description:BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM). BAP1 loss is common in UM and is associated with a worse prognosis. BAP1 loss is rare in CM and the outcome is unclear. UM and CM data was retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS). BAP1-low mRNA predicted a poor OS in UM (HR = 9.57, 95% CI: 2.82, 32.5) but a contrasting better OS in CM (HR = 0.73, 95% CI: 0.56, 0.95). These results remained unchanged after adjusting for sex, age, and stage in UM and CM, or after adjusting for ulceration or Breslow depth in CM. Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients. Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors. Low BAP1 mRNA was significantly associated with a better OS in CM patients, in sharp contrast to UM. High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients. Function of BAP1 was largely different in CM and UM despite of a small subset of shared co-expressed genes.
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Project description:ImportanceEarly-stage melanoma, among the most common cancers in the US, is typically treated with wide local excision. However, recent advances in immunohistochemistry have led to an increasing number of these cases being excised via Mohs micrographic surgery (MMS). Although studies of resections for other cancers have reported that facility-level factors are associated with patient outcomes, it is not yet established how these factors may affect outcomes for patients treated with Mohs micrographic surgery.ObjectiveTo evaluate the association of treatment center academic affiliation and case volume with long-term patient survival after MMS for T1a-T2a invasive melanoma.Design, setting, and participantsIn a retrospective cohort study, 4062 adults with nonmetastatic, T1a-T2a melanoma diagnosed from 2004 to 2014 and treated with MMS in the National Cancer Database (NCDB) were identified. The NCDB includes all reportable cases from Commission on Cancer-accredited facilities and is estimated to capture approximately 50% of all incident melanomas in the US. Multivariable survival analyses were conducted using Cox proportional hazards models. Data analysis was conducted from February 27 to August 18, 2020.ExposuresTreatment facility characteristics.Main outcomes and measuresOverall survival.ResultsThe study population included 4062 patients (2213 [54.5%] men; median [SD] age, 60 [16.3] years) treated at 462 centers. Sixty-two centers were top decile-volume facilities (TDVFs), which treated 1757 patients (61.9%). Most TDVFs were academic institutions (37 of 62 [59.7%]). On multivariable analysis, treatment at an academic center was associated with a nearly 30% reduction in hazard of death (hazard ratio, 0.730; 95% CI, 0.596-0.895). In a separate analysis, treatment at TDVFs was also associated with improved survival (hazard ratio, 0.795; 95% CI, 0.648-0.977).Conclusions and relevanceIn this cohort study, treatment of patients with T1a-T2a invasive melanoma excised with MMS at academic and top decile-volume (≥8 cases per year) facilities was associated with improved long-term survival compared with those excised by MMS at nonacademic and low-volume facilities. Identification and protocolization of the practices of these facilities may help to reduce survival differences between centers.
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Project description:BackgroundDespite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival.MethodsA retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis.ResultsA total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively.ConclusionsDevelopment of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death.Plain language summaryMetastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.
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Project description:BackgroundTebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.MethodsWe report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival.ResultsAt a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred.ConclusionsThis 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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Project description:Background: Nucleolar and spindle-associated protein 1 (NUSAP1) was previously reported to be associated with poor prognosis in multiple cancers. In the present study, we comprehensively investigated the clinicopathological features and potential prognostic value of NUSAP1 in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods: The expression profiles of the genes were extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Cancer Cell Line Encyclopedia (CCLE), Gene Expression Profiling Interactive Analysis (GEPIA), and The Human Protein Atlas databases. The association between clinicopathological characteristics and NUSAP1 was analyzed using logistic regression in TCGA patients and receiver operating characteristic (ROC) curve analysis for GSE7803, GSE9750, and GSE63514 datasets. The prognostic value of NUSAP1 in TCGA patients was evaluated using the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. Results: A total of 68 differentially expressed genes (DEGs) were identified in CESC. ROC analysis of NUSAP1 suggested that the area under the ROC curve was 0.968. Kaplan-Meier survival analysis indicated that CESC with low expression of NUSAP1 has a worse prognosis than CESC with high NUSAP1 expression (P = 0.005). The logistic regression revealed that low NUSAP1 expression in CESC was related to advanced tumor stage in TCGA database. Moreover, Cox regression analysis showed that NUSAP1 expression correlated significantly with prognosis in the case of patients in TCGA database. GSEA demonstrated that CESC patients with high expression of NUSAP1 were enriched in the G2M checkpoint, MYC targets, and breast cancer ZNF217. Conclusion: The results suggest that identification of DEGs might enhance our understanding of the causes and molecular mechanisms underlying the development of CESC. Moreover, NUSAP1 may play an important role in CESC progression and prognosis and may serve as a valuable indicator of poor survival in CESC.
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Project description:BackgroundFavorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival.MethodsWe used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable.ResultsA total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival.ConclusionsAs the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum.
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