Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism
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ABSTRACT:
PROVIDER: PRJNA646477 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12228600.fastq.gz | Fastqsanger.gz | |||
| SRR12228601.fastq.gz | Fastqsanger.gz | |||
| SRR12228602.fastq.gz | Fastqsanger.gz | |||
| SRR12228603.fastq.gz | Fastqsanger.gz | |||
| SRR12228604.fastq.gz | Fastqsanger.gz |
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Project description:ABSTRACT Metastases are often the direct cause of death of patients with pancreatic ductal adenocarcinoma (PDAC). Yet, the role of genomic alterations in mediating tropism and metastasis formation by pancreatic cancer cells is currently unknown. We aimed to identify genomic alterations predisposing colonization of PDAC cells to distant organs and decipher mechanisms enabling this process. Methods: Frequency of genomic alterations was assessed in 2668 local-biopsied compared to 2840 metastatic PDAC samples. Tumorigenic phenotype and transcriptomic profile of manipulated PDAC cells was assessed. Results: The prevalence of genomic alterations was site dependent, with different profiles observed in samples obtained from the pancreas compared to those obtained from the liver, lungs or lymph nodes. Liver metastases were characterized by deletion of the cyclin dependent kinase inhibitors 2A/2B (CDKN2A/B, encoding p16 and p15, respectively). Studies in PDAC cells indicated enhanced growth under liver conditions following p16/15 deletion. The liver is characterized by high ammonia-low glutamine environment, and a transcriptomic assay revealed modulation of glutamine-ammonia pathway-related genes by p15/p16. Accordingly, p15/p16 deletion promoted growth under high ammonia-low glutamine condition, upregulated glutamate-ammonia ligase (GLUL) and downregulated glutaminase 2 (GLS2). Importantly, GLUL-silencing had a more pronounced effect on proliferation of p15/p16-deleted PDAC cells. Conclusion: These data suggest a unique role for genomic alterations in mediating tropism and metastases formation. Among these alterations, p15/16 loss was identified as a promoter of liver metastases and further studies indicated a novel role for p16/15, namely, regulation of glutamine synthesis. These findings may pave the way for the development of novel therapeutic strategies aiming at the prevention of liver metastases formation.
2023-07-06 | GSE154492 | GEO
Project description:The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7x10-5 (AUC>0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 x 10-25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1x10-5 (AUC=0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change=48.5, P<9x10-24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P=5.8x10-6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P=0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.
2024-05-07 | GSE266478 | GEO
Project description:lncRNA CDKN2B-AS1 regulates collagen expression
| PRJNA1107262 | ENA
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis. Aorta and macrophages from ten C57BL/6.MOLFc4(51Mb)-Ldlr-/- mice and their control C57BL/6-Ldlr-/- were obtained, RNA purified and hybridized to GPL9734 Affimetrix microarrays.
2011-09-30 | E-GEOD-24342 | biostudies-arrayexpress
Project description:This study demonstrates a critical role for CDKN2B inactivation in the development of pancreatic cancer and provides a potential adult animal model by mimicking the frequent genetic alterations of human pancreatic cancer in fully mature adult mouse.
2016-11-09 | GSE87388 | GEO
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis.
2011-10-01 | GSE24342 | GEO
Project description:The aim of the present study was to investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation-specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non-CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73±5.88 vs. 62.62±5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26±5.48 vs. 58.33±7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation.
| S-EPMC5740815 | biostudies-other
Project description:We show that gene expression change of CDKN2B-AS1 overexpressed SH-SY5Y neuroblastoma cells.
2024-05-17 | GSE236621 | GEO
Project description:OBJECTIVE:Worldwide, the highest frequencies of APOL1-associated kidney variants are found in indigenous West Africans among whom small vessel disease (SVD) ischemic stroke is the most common stroke phenotype. The objective of this study was to investigate the association and effect sizes of 23 selected SNPs in 14 genes of relevance, including the APOL1 G1 variants, with the occurrence of SVD ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. MATERIALS AND METHODS:Cases were consecutively recruited consenting adults (aged 18 years or older) with neuroimaging-confirmed first clinical stroke. Stroke-free controls were ascertained using a locally validated version of the Questionnaire for Verifying Stroke-Free Status (QVSFS). Logistic regression models adjusting for known vascular risk factors were fitted to assess the associations of the 23 SNPs in rigorously phenotyped cases (N = 154) of SVD ischemic stroke and stroke-free (N = 483) controls. RESULTS:Apolipoprotein L1 (APOL1) rs73885319 (OR = 1.52; CI: 1.09-2.13, P-value = .013), rs2383207 in CDKN2A/CDKN2B (OR = 3.08; CI: 1.15-8.26, P -value = .026) and rs2107595 (OR = 1.70; CI: 1.12-2.60, P-value = .014) and rs28688791 (OR = 1.52; CI: 1.03-2.26, P-value = .036) in HDAC9 gene were associated with SVD stroke at 0.05 significance level. Polymorphisms in other genes did not show significant associations. CONCLUSION:This is the first report of a specific association of APOL1 with a stroke subtype. Further research is needed to confirm these initial findings and deepen understanding of the genetics of stroke in people of African ancestry with possible implications for other ancestries as all humans originated from Africa.
| S-EPMC5716854 | biostudies-literature
Project description:The association between the rs4977756 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta-analysis. A comprehensive literature search was performed using PubMed and EMBASE database. Six articles including 12 case-control studies in English with 12022 controls and 6871 cases were eligible for the meta-analysis. Subgroup analyses were conducted by ethnicity and source of controls. Our meta-analysis found that rs4977756 polymorphism was associated with glioma risks in homozygote, heterozygote, dominant, recessive and additive genetic models (GG versus AA: OR=1.55, 95% CI=1.42-1.69, Ph=0.996, I(2)=0.0%; AG versus AA: OR=1.20, 95% CI=1.12-1.28, Ph=0.934, I(2)=0.0%; recessive model: OR=1.39, 95% CI=1.28-1.50, Ph=0.995, I(2)=0.0%; dominant model: OR=1.29, 95% CI=1.21-1.37, Ph=0.923, I(2)=0.0%; additive model: OR=1.24, 95% CI=1.19-1.30, Ph=0.966, I(2)=0.0%). Moreover, our results suggested that CDKN2A-CDKN2B rs4977756 polymorphism was associated with a notable increased risk of glioma in Europeans. However, in Asians, we could not come to a conclusion because of lack of studies. Sensitivity analysis showed the omission of any study made no significant difference. No evidence of publication bias was produced. Our meta-analysis suggested that rs4977756 polymorphism was associated with increased risk of glioma. Moreover, additional studies should be further investigated to draw a more accurate conclusion.
| S-EPMC4694238 | biostudies-literature