scholarly journals CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

2019 ◽  
Author(s):  
Megan L. Insco ◽  
Brian J. Abraham ◽  
Sara J. Dubbury ◽  
Sofia Dust ◽  
Constance Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Rna Polymerase Ii ◽  
Kinase Activity ◽  
Prognostic Significance ◽  
Rna Degradation ◽  
Poor Overall Survival ◽  
Cyclin Dependent Kinases ◽  
Nuclear Rna ◽  
Melanoma Patients

AbstractTranscriptional Cyclin Dependent Kinases modulate RNA Polymerase II function to impact gene expression. Here, we show that CDK13 is mutated in 4% of patient melanomas and mutation or downregulation is associated with poor overall survival. Mutant CDK13 lacks kinase activity and overexpression in zebrafish leads to accelerated melanoma. CDK13 mutant fish and human melanomas accumulate prematurely terminated RNAs that are translated into truncated proteins. CDK13 binds to and regulates the phosphorylation of ZC3H14, a member of the PolyA eXosome Targeting (PAXT) RNA degradation complex. ZC3H14 phosphorylation recruits the PAXT complex to degrade prematurely terminated polyadenylated transcripts in the nucleus. In the presence of mutant CDK13, ZC3H14 phosphorylation is compromised and consequently fails to recruit the PAXT complex, leading to truncated transcript stabilization. This work establishes a role for CDK13 and the PAXT nuclear RNA degradation complex in cancer and has prognostic significance for melanoma patients with mutated or downregulated CDK13.

scholarly journals Network analysis identifies DAPK3 as a potential biomarker for lymphovascular invasion and prognosis of colon adenocarcinoma

2021 ◽  
Author(s):  
Huey-Miin Chen ◽  
Justin A. MacDonald
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Network Analysis ◽  
Gene Networks ◽  
Lymphovascular Invasion ◽  
Prognostic Significance ◽  
Colon Adenocarcinoma ◽  
Poor Overall Survival ◽  
Potential Biomarker ◽  
Mesenchymal Transformation

AbstractAdenocarcinoma of the colon is the fourth most common malignancy worldwide with significant rates of mortality. Hence, the identification of novel molecular biomarkers with prognostic significance is of particular importance for improvements in treatment and patient outcome. Clinical traits and RNA-Seq data of 551 patient samples and 18,205 genes in the UCSC Toil Recompute Compendium of TCGA TARGET and GTEx datasets (restricted to |Primary_site| = colon) were obtained from the Xena platform. Weighted gene co-expression network analysis was completed, and 24 unique modules were assembled to specifically examine the association between gene networks and cancer cell invasion. One module, containing 151 genes, was significantly correlated with lymphatic invasion, a histopathological feature of higher-risk colon cancer. Search tool for the retrieval of interacting genes/proteins (STRING) and gene ontology (GO) analyses identified the module to be enriched in genes related to cytoskeletal organization and apoptotic signaling, suggesting involvement in tumor cell survival and migration along with epithelial-mesenchymal transformation. Of genes that were differentially expressed and significant for overall survival, DAPK3 (death-associated protein kinase 3) was revealed as the pseudo-hub of the module. Although DAPK3 expression was reduced in colon cancer patients, survival analysis revealed that high expression of DAPK3 was significantly correlated with greater lymphovascular invasion and poor overall survival.

scholarly journals Prognostic and clinicopathological significance of pretreatment mean platelet volume in cancer: a meta-analysis

BMJ Open ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. e037614
Author(s):  
Xin Chen ◽  
Jing Li ◽  
Xunlei Zhang ◽  
Yushan Liu ◽  
Jindong Wu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mean Platelet Volume ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Clinicopathological Parameters ◽  
Platelet Volume ◽  
Poor Overall Survival ◽  
Patients With Cancer ◽  
Clinicopathological Significance

ObjectiveOur study aimed to evaluate the prognostic and clinicopathological significance of pretreatment mean platelet volume (MPV) on cancer by using meta-analysis of published studies.DesignMeta-analysis.Data sourcesRelevant studies available before 22 December 2019 were identified by searching MEDLINE, EMBASE.Eligibility criteriaAll published studies that assessed the prognostic and clinicopathological significance of pretreatment MPV on cancer were included.Data extraction and synthesisStudies were identified and extracted by two reviewers independently. The HR/OR and its 95% CIs of survival outcomes and clinicopathological parameters were calculated.ResultsA total of 38 eligible studies (41 subsets) with 9894 patients with cancer were included in the final meta-analysis. MPV level was not significantly associated with both overall survival (HR 0.98, 95% CI 0.84 to 1.14) and disease-free survival (HR 1.22, 95% CI 0.86 to 1.73) of patients with cancer. Neither advanced nor mixed-stage tumour patients showed significant association between MPV and overall survival (HR 1.36, 95% CI 0.96 to 1.94, HR 0.90, 95% CI 0.74 to 1.09). However, high MPV had the strongest relationship with poor overall survival (HR 2.01; 95% CI 1.08 to 3.41) in gastric cancer, followed by pancreatic cancer (HR 1.54; 95% CI 1.31 to 1.82). Whereas in the subgroup using receiver operating characteristic curve method to define cut-off values, low MPV was significantly related to poor overall survival (HR 0.78, 95% CI 0.64 to 0.95). In addition, MPV had no significant association with age (OR 0.96, 95% CI 0.90 to 1.02), sex (OR 1.04, 95% CI 1.00 to 1.09), depth of cancer invasion (OR 0.90, 95% CI 0.77 to 1.04) and tumour stage (OR 0.91, 95% CI 0.78 to 1.07).ConclusionsPretreatment MPV level is of no clearly prognostic significance in cancers and no significant association with clinicopathological parameters of patients with cancers.

scholarly journals A Nomogram Based on a Three-Gene Signature Derived from AATF Coexpressed Genes Predicts Overall Survival of Hepatocellular Carcinoma Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Jun Liu ◽  
Jianjun Lu ◽  
Zhanzhong Ma ◽  
Wenli Li
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Clinical Practice ◽  
Correlation Coefficient ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Cancer Genome ◽  
Survival Prediction

Background. Hepatocellular carcinoma (HCC) is a common cancer with an extremely high mortality rate. Therefore, there is an urgent need in screening key biomarkers of HCC to predict the prognosis and develop more individual treatments. Recently, AATF is reported to be an important factor contributing to HCC. Methods. We aimed to establish a gene signature to predict overall survival of HCC patients. Firstly, we examined the expression level of AATF in the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the International Union of Cancer Genome (ICGC) databases. Genes coexpressed with AATF were identified in the TCGA dataset by the Poisson correlation coefficient and used to establish a gene signature for survival prediction. The prognostic significance of this gene signature was then validated in the ICGC dataset and used to build a combined prognostic model for clinical practice. Results. Gene expression data and clinical information of 2521 HCC patients were downloaded from three public databases. AATF expression in HCC tissue was higher than that in matched normal liver tissues. 644 genes coexpressed with AATF were identified by the Poisson correlation coefficient and used to establish a three-gene signature (KIF20A, UCK2, and SLC41A3) by the univariate and multivariate least absolute shrinkage and selection operator Cox regression analyses. This three-gene signature was then used to build a combined nomogram for clinical practice. Conclusion. This integrated nomogram based on the three-gene signature can predict overall survival for HCC patients well. The three-gene signature may be a potential therapeutic target in HCC.

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

2018 ◽  
Vol 71 (9) ◽  
pp. 787-794 ◽  
Author(s):  
Stephanie Robertson ◽  
Gustav Stålhammar ◽  
Eva Darai-Ramqvist ◽  
Mattias Rantalainen ◽  
Nicholas P Tobin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Survival Data ◽  
Prognostic Value ◽  
Molecular Subtype ◽  
Axillary Lymph Node Metastasis ◽  
Axillary Lymph ◽  
Poor Overall Survival ◽  
Breast Tumours

AimsThe accuracy of biomarker assessment in breast pathology is vital for therapy decisions. The therapy predictive and prognostic biomarkers oestrogen receptor (ER), progesterone receptor, HER2 and Ki67 may act as surrogates to gene expression profiling of breast cancer. The aims of this study were to investigate the concordance of consecutive biomarker assessment by immunocytochemistry on preoperative fine-needle aspiration cytology versus immunohistochemistry (IHC) on the corresponding resected breast tumours. Further, to investigate the concordance with molecular subtype and correlation to stage and outcome.MethodsTwo retrospective cohorts comprising 385 breast tumours with clinicopathological data including gene expression-based subtype and up to 10-year overall survival data were evaluated.ResultsIn both cohorts, we identified a substantial variation in Ki67 index between cytology and histology and a switch between low and high proliferation within the same tumour in 121/360 cases. ER evaluations were discordant in only 1.5% of the tumours. From cohort 2, gene expression data with PAM50 subtype were used to correlate surrogate subtypes. IHC-based surrogate classification could identify the correct molecular subtype in 60% and 64% of patients by cytology (n=63) and surgical resections (n=73), respectively. Furthermore, high Ki67 in surgical resections but not in cytology was associated with poor overall survival and higher probability for axillary lymph node metastasis.ConclusionsThis study shows considerable differences in the prognostic value of Ki67 but not ER in breast cancer depending on the diagnostic method. Furthermore, our findings show that both methods are insufficient in predicting true molecular subtypes.

scholarly journals Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 104 ◽  
Author(s):  
Dmitry A. Kretov ◽  
Daria A. Mordovkina ◽  
Irina A. Eliseeva ◽  
Dmitry N. Lyabin ◽  
Dmitry N. Polyakov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Localization ◽  
Kinase Activity ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Regulatory Mechanisms ◽  
Nuclear Accumulation ◽  
Nuclear Retention ◽  
Post Translational Modifications

The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.

scholarly journals Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Michal Lotem ◽  
Sharon Merims ◽  
Stephen Frank ◽  
Tamar Hamburger ◽  
Aviram Nissan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Disease Recurrence ◽  
Gene Signature ◽  
Melanoma Cells ◽  
Delayed Type Hypersensitivity ◽  
Strong Response ◽  
Expression Array ◽  
Melanoma Vaccine ◽  
Melanoma Patients

Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence.Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival.Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p=0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p=0.007).Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.

scholarly journals Gene expression amplification by nuclear speckle association

2019 ◽  
pp. jcb.201904046 ◽  
Author(s):  
Jiah Kim ◽  
Neha Chivukula Venkata ◽  
Gabriela Andrea Hernandez Gonzalez ◽  
Nimish Khanna ◽  
Andrew S. Belmont
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Liquid Droplet ◽  
Transcript Level ◽  
Rna Degradation ◽  
Nuclear Speckles ◽  
Nascent Transcript ◽  
Nuclear Compartment ◽  
Transcript Levels ◽  
Endogenous Genes

Many active genes reproducibly position near nuclear speckles, but the functional significance of this positioning is unknown. Here we show that HSPA1B BAC transgenes and endogenous Hsp70 genes turn on 2–4 min after heat shock (HS), irrespective of their distance to speckles. However, both total HSPA1B mRNA counts and nascent transcript levels measured adjacent to the transgene are approximately twofold higher for speckle-associated alleles 15 min after HS. Nascent transcript level fold-increases for speckle-associated alleles are 12–56-fold and 3–7-fold higher 1–2 h after HS for HSPA1B transgenes and endogenous genes, respectively. Severalfold higher nascent transcript levels for several Hsp70 flanking genes also correlate with speckle association at 37°C. Live-cell imaging reveals that HSPA1B nascent transcript levels increase/decrease with speckle association/disassociation. Initial investigation reveals that increased nascent transcript levels accompanying speckle association correlate with reduced exosome RNA degradation and larger Ser2p CTD-modified RNA polymerase II foci. Our results demonstrate stochastic gene expression dependent on positioning relative to a liquid-droplet nuclear compartment through “gene expression amplification.”

Prognostic significance of children with cutaneous melanoma: Implications for treatment

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8021-8021
Author(s):  
M. A. Kavanagh ◽  
R. Essner ◽  
S. L. Chen ◽  
L. A. Wanek ◽  
R. P. Scheri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cutaneous Melanoma ◽  
Pediatric Patients ◽  
Prognostic Significance ◽  
Initial Diagnosis ◽  
Adult Patients ◽  
Breslow Thickness ◽  
Superficial Spreading ◽  
Clark Level ◽  
Melanoma Patients

8021 Background: The incidence of melanoma in pediatric patients, particularly teenagers, is increasing. Treatment strategies employed for adult patients with melanoma have been applied to pediatric populations with minimal data to support similar efficacy. We performed a matched-paired analysis to compare the prognosis of pediatric (≤19 yrs old) and adult melanoma patients. Methods: Single institution, prospectively obtained melanoma database containing >14,000 records was queried for children ages 1–19 years treated for cutaneous melanoma. We identified 197 pediatric patients seen at our institute over the last 35 years. After excluding patients not seen within 4 months of initial diagnosis, 115 pediatric patients were matched to adults (age 20–70 years) chosen from the database by gender, stage, primary site and tumor characteristics (Clark level, Breslow thickness, and ulceration). Overall survival was compared between cohorts by the Kaplan-Meier method. Results: For the pediatric patients, median age at diagnosis was 17.7 years (range 7–19 years). Patients were almost equally distributed between girls (47%) and boys. AJCC stage I and II disease at presentation was most common (73%), with stage III and IV occurring much less frequently (25% and 2%). Most pediatric patients had Clark level IV (37%) lesions; Clark level II (25%), III (25%), V (4%), and I (2%) lesions were less common. Breslow thickness ranged between <1.0mm (38%), 1.1–2.0mm (20%), 2.1–4.0mm (17%), and >4.1mm (12%). The two predominant histologic types were superficial spreading (52%) and nodular (22%) melanoma. 14% of the primary lesions were ulcerated. Rates of disease-free and overall survival were 75%± 4% and 84%± 4% at 5 years and 74%± 4% and 77%± 5% at 10 years, respectively, with a median follow up of 5.1 years (range 1–30 years). Matched pediatric and adult patients showed no difference in survival from time of initial diagnosis and stage of presentation (log rank p=0.24). Conclusions: Stage-specific survival in pediatric and adult melanoma patients is similar. In the absence of specific pediatric trials, standard treatment for children with melanoma should be consistent with that for adults. No significant financial relationships to disclose.

Quantitative analysis of intrahepatic hepatitis B (HBV) DNA and cccDNA and their impact on survival posthepatectomy in HBV-associated hepatocellular carcinoma (HCC) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14583-e14583
Author(s):  
Qin Wang ◽  
Wei Luan ◽  
M. Isabel Fiel ◽  
Sima Blank ◽  
Ki Won Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Resection ◽  
Cox Regression ◽  
Activity Index ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Hbv Dna ◽  
Tumor Diameter ◽  
Poor Overall Survival ◽  
Large Tumor

e14583 Background: Little is known about the prognostic significance of total intrahepatic HBV DNA (ihHBV DNA) and cccDNA, a stable episome that accumulates in the nuclei and serves as the template for viral replication. This study aims to quantitate ihHBV DNA and cccDNA in the non-neoplastic liver and to assess their impact on prognosis in HBV-HCC patients. Methods: 111 patients, many on HBV antivirals, who underwent liver resection for HBV-HCC from 1991 to 2008 were assessed by real time PCR for ihHBV DNA, cccDNA, and albumin. Liver fibrosis and necroinflammation was assessed using the modified Ishak method. Independent variables associated with survival were analyzed using multivariate Cox regression model, with a median follow up for survivors of 52 months. Results: Serum HBV DNA was detectable in only 42% of patients, but 106 patients (95%) had detectable ihHBV DNA (median: 0.018copy/hepatocyte); and 89 patients (80%) had detectable cccDNA (0.00058 copy/hepatocyte). Median cccDNA/ihHBV DNA ratio was 0.019. ihHBV DNA correlated with histologic activity index (p = 0.04) and serum ALT (p = 0.004). Patients in the lowest quartile of cccDNA/ihHBV DNA ratio (<0.0032) trended towards poor overall 5-year survival by univariate analysis (p = 0.09), with higher mortality at 2 years (89% vs. 45%, p = 0.03). In multivariate analysis, AFP > 20, Ishak fibrosis stage 6 (established cirrhosis), cccDNA/ihHBV DNA < 0.0032, and large tumor diameter were independently associated with poor overall survival (Table). Conclusions: ihHBV DNA levels were associated with severity of liver necroinflammation and injury. ihHBV DNA and cccDNA levels were not associated with survival; rather, low proportion of total HBV DNA in the form of cccDNA was independently associated with poor overall survival. Thus, viral behavior at the time of liver resection influences clinical outcome for HBV-HCC patients. [Table: see text]

Consensus gene expression analysis to identify key hallmarks of cancer in malignant melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21045-e21045
Author(s):  
Emma O'Connor ◽  
Eileen E. Parkes ◽  
Leeona Galligan ◽  
James Bradford ◽  
Shauna Lambe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Gene Expression Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Software Tool ◽  
Rna Seq ◽  
Combination Therapies ◽  
Hallmarks Of Cancer ◽  
Mesenchymal Transition ◽  
Melanoma Patients

e21045 Background: Traditionally gene expression signatures (GES) are used individually to classify patients into subgroups. Signatures targeting the same biology are often developed independently and may not classify identically. We developed the claraT software tool that uses consensus between multiple published GES categorised by the Hallmarks of Cancer (Hanahan & Weinberg, 2011) to classify cancers. As metastatic melanoma represents poor prognostic disease (5-yr survival 15-20%), we applied claraT to the TCGA melanoma dataset to identify targetable biologies, validated in a cohort of melanoma patients treated with Ipilimumab. Methods: TCGA RNA-seq data ( n= 472) was analysed using the claraT platform including GES for immune ( n= 14), angiogenesis ( n= 9) and epithelial-mesenchymal transition (EMT) ( n= 12) Hallmarks. Samples were clustered for the combined and individual Hallmarks. Median progression-free (PFS) and overall-survival (OS) differences were analysed across identified subgroups. Analysis was validated in an Ipilimumab treated melanoma dataset ( n= 42) (Van Allen, 2015). Results: Clustering the combined Hallmarks identified 4 subgroups in the TCGA cohort: 1) Immune active, 2) Immune-EMT active, 3) EMT-Angiogenesis active, 4) All inactive. Groups 1&2 had significantly improved OS compared to Groups 3&4 (HR = 0.50, p< 0.0001). Clustering using single Hallmarks revealed that immune-positive tumours had significantly improved OS (HR = 0.53, p< 0.0001) compared to immune-negative tumours. Angiogenesis-negative tumours displayed improved PFS (HR = 0.73, p= 0.03) and OS (HR = 0.53, p <0.0001) compared to angiogenesis-negative tumours. Interestingly the EMT Hallmark was not found to be individually prognostic. When validated in the Ipilimumab treated dataset, patients classified as immune-positive had improved OS (HR = 0.357, p= 0.010) when compared to immune-negative. Similar trends were also observed for angiogenesis and EMT Hallmarks. Conclusions: This study demonstrates how simultaneous analysis of multiple GES ( n= 35 in this study) can identify robust biologies through consensus expression. This platform may have value in the identification of reliable biomarkers for clinical trials and could inform how combination therapies targeting key biologies may be used in cancer treatment.

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