Genomic landscape of pancreatic adenocarcinoma: Does age matter?

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 250-250
Author(s):  
Irit Ben-Aharon ◽  
Moshe Elkabets ◽  
Raphael Pelossof ◽  
Kenneth H. Yu ◽  
Peter J. Allen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pancreatic Adenocarcinoma ◽  
Early Onset ◽  
Age Groups ◽  
The Cancer Genome Atlas ◽  
Three Samples ◽  
Genomic Analyses ◽  
Cellular Pathways ◽  
Tcga Dataset ◽  
Molecular Landscape

250 Background: State-of the art genomic analyses of pancreatic adenocarcinoma (PDAC) has yielded insights into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine if early-onset PDAC ( ≤ 55 yrs) displays a distinctive molecular landscape from average-age onset PDAC ( ≥ 70 yrs). Methods: Three distinct datasets of PDAC in age groups ≤ 55 and ≥ 70 years old were analyzed. In the first, patients undergoing treatment at MSKCC were consented for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) next generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression and protein expression. The third dataset was the Australian cohort of PDAC (Waddell et al, Nature, 2015). Clinical data were correlated with genomic analyses. Results: One hundred and eighty-three samples were analyzed, yielding N = 56 patients (pts) aged ≤ 55 years and N = 127 pts aged ≥ 70 years. Several genes known to be associated with carcinogenesis differed in mutation frequency across age groups: SMAD4, MYC and PIK3CA displayed higher mutation rates in younger patients (p < 0.05, table below). Comprehensive analysis by cellular pathways indicated that the PI3Kpathway is further altered in the younger population. Protein expression had different patterns in younger versus older patients. Smoking was more prevalent in the early-onset group in all three cohorts (59% vs. 47%). Survival outcomes revealed no differences between the age groups. Conclusions: This exploratory analysis suggests that there may be somatic gene alterations within the population of early onset PDAC patients that involve unique cellular pathways compared with average onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future analysis to support this observation. [Table: see text]

scholarly journals High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer

2021 ◽  
Author(s):  
Jeong Eun Kim ◽  
Jaeyong Choi ◽  
Chang-Ohk Sung ◽  
Yong Sang Hong ◽  
Sun Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Large Scale ◽  
Late Onset ◽  
Age Groups ◽  
The Cancer Genome Atlas ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Early Onset Colorectal Cancer

AbstractThe global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

scholarly journals Identification of glycolysis related pathways in pancreatic adenocarcinoma and liver hepatocellular carcinoma based on TCGA and GEO datasets

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ji Li ◽  
Chen Zhu ◽  
Peipei Yue ◽  
Tianyu Zheng ◽  
Yan Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Energy Metabolism ◽  
Pancreatic Adenocarcinoma ◽  
Digestive System ◽  
Prognostic Significance ◽  
R Package ◽  
The Cancer Genome Atlas ◽  
System Structure ◽  
Liver Hepatocellular Carcinoma

Abstract Background Abnormal energy metabolism is one of the characteristics of tumor cells, and it is also a research hotspot in recent years. Due to the complexity of digestive system structure, the frequency of tumor is relatively high. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms. Methods Gene set variance analysis (GSVA) R package was used to establish the metabolic score, and the score was used to represent the metabolic level. The relationship between the metabolism and prognosis of digestive system tumors was explored using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Volcano plots and gene ontology (GO) analyze were used to show different genes and different functions enriched between different glycolysis levels, and GSEA was used to analyze the pathway enrichment. Nomogram was constructed by R package based on gene characteristics and clinical parameters. qPCR and Western Blot were applied to analyze gene expression. All statistical analyses were conducted using SPSS, GraphPad Prism 7, and R software. All validated experiments were performed three times independently. Results High glycolysis metabolism score was significantly associated with poor prognosis in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). The STAT3 (signal transducer and activator of transcription 3) and YAP1 (Yes1-associated transcriptional regulator) pathways were the most critical signaling pathways in glycolysis modulation in PAAD and LIHC, respectively. Interestingly, elevated glycolysis levels could also enhance STAT3 and YAP1 activity in PAAD and LIHC cells, respectively, forming a positive feedback loop. Conclusions Our results may provide new insights into the indispensable role of glycolysis metabolism in digestive system tumors and guide the direction of future metabolism–signaling target combined therapy.

scholarly journals Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2487
Author(s):  
Chao Gao ◽  
Guangxu Jin ◽  
Elizabeth Forbes ◽  
Lingegowda S. Mangala ◽  
Yingmei Wang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Endometrial Cancer ◽  
Protein Interactions ◽  
Somatic Mutations ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Tcga Dataset ◽  
Inactivating Mutations

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK’s role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.

scholarly journals Comprehensive Analysis of ESRRA in Endometrial Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199208
Author(s):  
Shufang Wang ◽  
Xinlong Huo
Keyword(s):  
Endometrial Cancer ◽  
Protein Expression ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Operating Characteristics ◽  
Protein Expression Level ◽  
Normal Tissues

Background: Estrogen-related receptor alpha (ESRRA) was reported to play an important role in multiple biological processes of neoplastic diseases. The roles of ESRRA in endometrial cancer have not been fully investigated yet. Methods: Expression data and clinicopathological data of patients with uteri corpus endometrial carcinoma (UCEC) were obtained from The Cancer Genome Atlas (TCGA). Comprehensive bioinformatics analysis was performed, including receiver operating characteristics (ROC) curve analysis, Kaplan-Meier survival analysis, gene ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Immunohistochemistry was used to detect the protein expression level of ESRRA and CCK-8 assay was performed to evaluate the effect of ESRRA on the proliferation ability. Results: A total of 552 UCEC tissues and 35 normal tissues were obtained from the TCGA database. The mRNA and protein expression level of ESRRA was highly elevated in UCEC compared with normal tissues, and was closely associated with poor prognosis. ROC analysis indicated a very high diagnostic value of ESRRA for patients with UCEC. GO and GSEA functional analysis showed that ESRRA might be mainly involved in cellular metabolism processes, in turn, tumorigenesis and progression of UCEC. Knockdown of ESRRA inhibited the proliferation of UCEC cells in vitro. Further immune cell infiltration demonstrated that ESRRA enhanced the infiltration level of neutrophil cell and reduced that of T cell (CD4+ naïve), NK cell, and cancer associated fibroblast (CAF). The alteration of immune microenvironment will greatly help in developing immune checkpoint therapy for UCEC. Conclusions: Our study comprehensively analyzed the expression level, clinical value, and possible mechanisms of action of ESRRA in UCEC. These findings showed that ESRRA might be a potential diagnostic and therapeutic target.

Prognostic Value and Immune Infiltration of ARMC10 in Pancreatic Adenocarcinoma Via Integrated Bioinformatics Analyses

2021 ◽  
Author(s):  
Tianhao Li ◽  
Xiaohan Qin ◽  
Cheng Qin ◽  
Bangbo Zhao ◽  
Hongtao Cao ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Formation Rate ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Primary Therapy ◽  
Migration Ability ◽  
Bioinformatics Analyses ◽  
Immune Infiltration

Abstract Background: Armadillo repeat-containing 10 (ARMC10) is involved in the progression of multiple types of tumors. Pancreatic adenocarcinoma (PAAD) is a lethal disease with poor survival and prognosis.Methods: We acquired the data of ARMC10 in PAAD patients from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets and compared the expression level with normal pancreatic tissues. We evaluated the relevance between ARMC10 expression and clinicopathological factors, immune infiltration degree and prognosis in PAAD.Results: High expression of ARMC10 was relevant to T stage, M stage, pathologic stage, histologic grade, residual tumor, primary therapy outcome (P<0.05) and related to lower Overall-Survival (OS), Disease-Specific Survival (DSS), and Progression-Free Interval (PFI). Gene set enrichment analysis showed that ARMC10 was related to methylation in neural precursor cells (NPC), G alpha (i) signaling events, APC targets, energy metabolism, potassium channels and IL10 synthesis. The expression level of ARMC10 was positively related to the abundance of T helper cells and negatively to that of plasmacytoid dendritic cells (pDCs). Knocking down of ARMC10 could lead to lower proliferation, invasion, migration ability and colony formation rate of PAAD cells in vitro.Conclusions: Our research firstly discovered ARMC10 as a novel prognostic biomarker for PAAD patients and played a crucial role in immune regulation in PAAD.

scholarly journals Prevalence of Brucellosis in Dairy Cattle in Organized and Smallholder Farms in Some Selected Areas of Bangladesh

2014 ◽  
Vol 12 (2) ◽  
pp. 167-171
Author(s):  
MAS Sarker ◽  
MS Rahman ◽  
MT Islam ◽  
AKMA Rahman ◽  
MB Rahman ◽  
...  
Keyword(s):  
Age Groups ◽  
Dairy Farm ◽  
Economic Loss ◽  
Screening Tests ◽  
Ring Test ◽  
Serum Samples ◽  
Smallholder Farms ◽  
Three Samples ◽  
Holstein Friesian ◽  
Confirmatory Tests

Brucellosis causes a great economic loss to the livestock industries through abortion, infertility,birth of weak and dead offspring, increased calving interval and reduction of milk yield and it is endemic in Bangladesh. In this study we collected milk and blood samples simultaneously from533 cows of Central Cattle Breeding and Dairy Farm, Savar, Dhaka and different Upazilas of Gaibandha and Mymensingh District. Five hundred thirty three samples were examined for antibodies to Brucella using the Milk Ring Test (MRT) and Rose Bengal Test (RBT). Overall 2.62 % of milk samples were positive according to MRT, while2.06 % of the serum samples were positive to the RBT. Only 6 (1.13 %) of the samples were positive for both test (MRT and RBT). Out of 312 samples only 10 (3.20 %) were positive to MRT while 8(2.06%) were positive to RBT in Holstein Friesian cross (p>0.05) on the other hand out of 221 samples only 4 (1.80%) were positive to MRT while 3(1.35%) were positive to RBT in Sahiwal cross. The prevalence of brucellosis was significantly higher in the age group of > 5 years than other age groups (p?0.01) on both test (MRT 2.75%and RBT 2.25%).Based on parity, significantly higher prevalence (MRT 2.93% and RBT 2.44%) of MRT and RBT were obtainedin parity 3-5in comparison to other parity group (p?0.01). It is, however, obvious that although the MRT is 1st-line screening tests for brucellosis in cows in some countries, their lack of specificity is of concern. Therefore, the requirement for other confirmatory tests that are more specific should be used for the diagnosis of the disease, especially in Bangladesh.DOI: http://dx.doi.org/10.3329/bjvm.v12i2.21280 Bangl. J. Vet. Med. (2014). 12 (2): 167-171 

HMGA1 and HMGA2 protein expression correlates with advanced tumour grade and lymph node metastasis in pancreatic adenocarcinoma

2012 ◽  
Vol 60 (3) ◽  
pp. 397-404 ◽  
Author(s):  
Salvatore Piscuoglio ◽  
Inti Zlobec ◽  
Pierlorenzo Pallante ◽  
Romina Sepe ◽  
Francesco Esposito ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Protein Expression ◽  
Pancreatic Adenocarcinoma ◽  
Tumour Grade ◽  
Node Metastasis ◽  
Hmga2 Protein

scholarly journals Integrating Genetic and Transcriptomic Data to Reveal Pathogenesis and Prognostic Markers of Pancreatic Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaisong Bai ◽  
Tong Zhao ◽  
Yilong Li ◽  
Xinjian Li ◽  
Zhantian Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Adenocarcinoma ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Prognostic Markers ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Variation ◽  
The Cancer Genome Atlas ◽  
Driver Genes

Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies and mortality for PAAD have remained increasing under the conditions of substantial improvements in mortality for other major cancers. Although multiple of studies exists on PAAD, few studies have dissected the oncogenic mechanisms of PAAD based on genomic variation. In this study, we integrated somatic mutation data and gene expression profiles obtained by high-throughput sequencing to characterize the pathogenesis of PAAD. The mutation profile containing 182 samples with 25,470 somatic mutations was obtained from The Cancer Genome Atlas (TCGA). The mutation landscape was generated and somatic mutations in PAAD were found to have preference for mutation location. The combination of mutation matrix and gene expression profiles identified 31 driver genes that were closely associated with tumor cell invasion and apoptosis. Co-expression networks were constructed based on 461 genes significantly associated with driver genes and the hub gene FAM133A in the network was identified to be associated with tumor metastasis. Further, the cascade relationship of somatic mutation-Long non-coding RNA (lncRNA)-microRNA (miRNA) was constructed to reveal a new mechanism for the involvement of mutations in post-transcriptional regulation. We have also identified prognostic markers that are significantly associated with overall survival (OS) of PAAD patients and constructed a risk score model to identify patients’ survival risk. In summary, our study revealed the pathogenic mechanisms and prognostic markers of PAAD providing theoretical support for the development of precision medicine.

scholarly journals The Clinicopathological and Prognostic Significance of SOX9 Expression in Gastric Cancer: Meta-Analysis and TCGA Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Guo Zu ◽  
Jiacheng Gao ◽  
Tingting Zhou
Keyword(s):  
Gastric Cancer ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Tnm Stage ◽  
The Cancer Genome Atlas ◽  
Depth Of Invasion ◽  
Sox9 Expression ◽  
Potential Prognostic Factor ◽  
Clinicopathological Significance ◽  
Tcga Dataset

BackgroundThe clinicopathological and prognostic significance of SRY-box transcription factor 9 (SOX9) expression in gastric cancer (GC) patients is still controversial. Our aim is to investigate the clinicopathological and prognostic value of SOX9 expression in GC patients.MethodsA systemic literature search and meta-analysis were used to evaluate the clinicopathological significance and overall survival (OS) of SOX9 expression in GC patients. The Cancer Genome Atlas (TCGA) dataset was used to investigate the relationship between SOX9 expression and OS of stomach adenocarcinoma (STAD) patients.ResultsA total of 11 articles involving 3,060 GC patients were included. In GC patients, the SOX9 expression was not associated with age [odds ratio (OR) = 0.743, 95% CI = 0.507–1.089, p = 0.128], sex (OR = 0.794, 95% CI = 0.605–1.042, p = 0.097), differentiation (OR = 0.728, 95% CI = 0.475–1.115, p = 0.144), and lymph node metastasis (OR = 1.031, 95% CI = 0.793–1.340, p = 0.820). SOX9 expression was associated with depth of invasion (OR = 0.348, 95% CI = 0.247–0.489, p = 0.000) and TNM stage (OR = 0.428, 95% CI = 0.308–0.595, p = 0.000). The 1-year OS (OR = 1.507, 95% CI = 1.167–1.945, p = 0.002), 3-year OS (OR = 1.482, 95% CI = 1.189–1.847, p = 0.000), and 5-year OS (OR = 1.487, 95% CI = 1.187–1.862, p = 0.001) were significantly shorter in GC patients with high SOX9 expression. TCGA analysis showed that SOX9 was upregulated in STAD patients compared with that in normal patients (p &lt; 0.001), and the OS of STAD patients with a high expression of SOX9 is poorer than that in patients with low expression of SOX9, but the statistical difference is not obvious (p = 0.31).ConclusionSOX9 expression was associated with the depth of tumor invasion, TNM stage, and poor OS of GC patients. SOX9 may be a potential prognostic factor for GC patients but needs further study.Systematic Review RegistrationPROSPERO, ID NUMBER 275712.

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