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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation in CpG islands is associated with transcriptional silencing. Accurate determination of cytosine methylation status in promoter CpG dinucleotides may provide diagnostic and prognostic value for human cancers. We have developed a quantitative PCR/LDR/Universal Array assay that allows parallel evaluation of methylation status of 75 CpG dinucleotides in the promoter regions of 15 tumor suppressor genes (CDKN2B, CDKN2A, CDKN2D, CDKN1A, CDKN1B, TP53, BRCA1, TIMP3, APC, RASSF1, CDH1, MGMT, DAPK1, GSTP1, and RARB). When compared with an independent pyrosequencing method at a single promoter, the two approaches gave good correlation. In a study using 15 promoter regions and seven blinded tumor cell lines, our technology was capable of distinguishing methylation profiles that identified cancer cell lines derived from the same origins. Preliminary studies using 96 colorectal tumor samples and 73 matched normal tissues indicated CpG methylation is a gene-specific and nonrandom event in colon cancer. This new approach is suitable for clinical applications where sample quantity and purity can be limiting factors.
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PMID:Multiplexed profiling of candidate genes for CpG island methylation status using a flexible PCR/LDR/Universal Array assay. 1636 45

Studying the proliferative ability of human bone marrow derived mesenchymal stem cells in hypoxic conditions can help us achieve the effective regeneration of ischemic injured myocardium. Cardiac-type fatty acid binding protein (FABP3) is a specific biomarker of muscle and heart tissue injury. This protein is purported to be involved in early myocardial development, adult myocardial tissue repair and responsible for the modulation of cell growth and proliferation. We have investigated the role of FABP3 in human bone marrow derived mesenchymal stem cells under ischemic conditions. MSCs from 12 donors were cultured either in standard normoxic or modified hypoxic conditions, and the differential expression of FABP3 was tested by quantitative (RT)PCR and western blot. We also established stable FABP3 expression in MSCs and searched for variation in cellular proliferation and differentiation bioprocesses affected by hypoxic conditions. We identified: (1) the FABP3 differential expression pattern in the MSCs under hypoxic conditions; (2) over-expression of FABP3 inhibited the growth and proliferation of the MSCs; however, improved their survival in low oxygen environments; (3) the cell growth factors and positive cell cycle regulation genes, such as PCNA, APC, CCNB1, CCNB2 and CDC6 were all down-regulated; while the key negative cell cycle regulation genes TP53, BRCA1, CASP3 and CDKN1A were significantly up-regulated in the cells with FABP3 overexpression. Our data suggested that FABP3 was up-regulated under hypoxia; also negatively regulated the cell metabolic process and the mitotic cell cycle. Overexpression of FABP3 inhibited cell growth and proliferation via negative regulation of the cell cycle and down-regulation of cell growth factors, but enhances cell survival in hypoxic or ischemic conditions.
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PMID:Overexpression of FABP3 inhibits human bone marrow derived mesenchymal stem cell proliferation but enhances their survival in hypoxia. 2458 97

The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.
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PMID:A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India. 2494 87

Cervical cancer is primarily caused by Human papillomavirus (HPV) infection, but other factors such as smoking habits, co-infections and genetic background, can also contribute to its development. Although this cancer is avoidable, it is the fourth most frequent type of cancer in females worldwide and can only be treated with chemotherapy and radical surgery. There is a need for biomarkers that will enable early diagnosis and targeted therapy for this type of cancer. Therefore, a systems biology pipeline was applied in order to identify potential biomarkers for cervical cancer, which show significant reports in three molecular aspects: DNA sequence variants, DNA methylation pattern and alterations in mRNA/protein expression levels. CDH1, CDKN2A, RB1 and TP53 genes were selected as putative biomarkers, being involved in metastasis, cell cycle regulation and tumour suppression. Other ten genes (CDH13, FHIT, PTEN, MLH1, TP73, CDKN1A, CACNA2D2, TERT, WIF1, APC) seemed to play a role in cervical cancer, but the lack of studies prevented their inclusion as possible biomarkers. Our results highlight the importance of these genes. However, further studies should be performed to elucidate the impact of DNA sequence variants and/or epigenetic deregulation and altered expression of these genes in cervical carcinogenesis and their potential as biomarkers for cervical cancer diagnosis and prognosis.
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PMID:Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles. 2892 26

Eccrine porocarcinomas (EPs) are rare malignant tumours of the intraepidermic sweat gland duct and most often arise from benign eccrine poromas. Some recurrent somatic genomic events have been identified in these malignancies, but very little is known about the complexity of their molecular pathophysiology. We describe the whole genome and whole transcriptome genomic profiling of a metastatic EP in a 66-year-old male patient with a previous history of localized porocarcinoma of the scalp. Whole genome and whole transcriptome genomic profiling was performed on the metastatic EP. Whole genome sequencing was performed on blood-derived DNA in order to allow a comparison between germline and somatic events. We found somatic copy losses of several tumour suppressor genes including APC, PTEN and CDKN2A, CDKN2B and CDKN1A. We identified a somatic hemizygous CDKN2A pathogenic splice site variant. De novo transcriptome assembly revealed abnormal splicing of CDKN2A p14ARF and p16INK4a. Elevated expression of oncogenes EGFR and NOTCH1 was noted and no somatic mutations were found in these genes. Wnt pathway somatic alterations were also observed. In conclusion, our results suggest that the molecular pathophysiology of malignant EP features high complexity and subtle interactions of multiple key genes. Cell cycle dysregulation and CDKN2A loss of function was found to be a new potential driver in EP tumourigenesis. Moreover, the combination of somatic copy number variants and abnormal gene expression perhaps partly related to epigenetic mechanisms, all likely contribute to the development of this rare malignancy in our patient.
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PMID:Whole genome and whole transcriptome genomic profiling of a metastatic eccrine porocarcinoma. 2987 26

Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine, ClF), a second-generation 2'-deoxyadenosine analog, possesses manifold anti-cancer activities. Our previous reports and some of others demonstrate the potential capacity of ClF to regulate the epigenetic machinery. The study presented here is the first to investigate the influence of ClF on modulators of the DNA methylation machinery, including DNMT1 and CDKN1A, in acute lymphoblastic leukemia (ALL) cells. ClF effects on promoter methylation and transcriptional activity of hypermethylated and silenced tumor suppressor genes (TSGs), including APC, CDKN2A, PTEN, and RARB, have been tested as well. Methylation level of the proximal promoter region of APC, CDKN2A, PTEN, and RARB, as well as expression of those TSGs, DNMT1 and CDKN1A, were estimated by using a methylation-sensitive restriction analysis and qPCR, respectively. The Nalm-6 cell line was used as an experimental in vitro model of ALL cells. We observed ClF-mediated inhibition of cellular viability and apoptosis induction of Nalm-6 cells with an increased percentage of cells positive for active Caspase-3. Interestingly, exposure of Nalm-6 cells to CIF at 20 nM concentration for three days has led to a significant DNMT1 downregulation, accompanied by robust CDKN1A upregulation. ClF caused hypomethylation of APC, CDKN2A, and PTEN, with a concomitant increase in their transcript levels. Taken together, our results demonstrate the ability of ClF to reactivate DNA methylation-silenced TSGs in ALL cells. This may implicate translational significance of our findings and support ClF application as a new epigenetic modulator in the anti-leukemia therapy.
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PMID:The effects of clofarabine in ALL inhibition through DNA methylation regulation. 3199 20

A 41-yr-old, otherwise healthy, premenopausal woman presented at our uro-oncology clinic with a diagnosis of muscle-invasive bladder cancer following a transurethral resection of the bladder performed at another center. After a thorough discussion with the patient, she was enrolled in the phase II PURE-01 trial (NCT02736266), testing three cycles of neoadjuvant pembrolizumab (200mg) every 3 wk before radical cystectomy. Before treatment, imaging studies were obtained as per the protocol using computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT, and multiparametric magnetic resonance imaging of the bladder, defining a clinically localized T2N0M0 stage. As per the protocol, potential biomarkers were assessed, including PD-L1 expression (84% combined positive score), tumor mutational burden (16.67 mut/Mb), and genomic profiling (FoundationONE assay; somatic mutation in TP53, EZH2, APC, TERT, CDKN1A, CDKN1B, and ARID1A genes, and truncation in BRCA2 gene). After immunotherapy, the patient underwent a robot-assisted radical cystectomy with extended pelvic lymph node dissection. The final pathology report revealed absence of residual disease (ie, pathological complete response, ypT0ypN0). During follow-up, the only relevant and permanent immune-mediated adverse event was hypothyroidism secondary to an autoimmune thyroiditis. It appeared 2 mo after radical cystectomy and it was managed successfully with hormonal replacement therapy. Two years after treatment, the patient is asymptomatic and free from disease recurrence. PATIENT SUMMARY: Increasing evidence suggests that frontline neoadjuvant immunotherapy may be beneficial for patients diagnosed with non-locally advanced, muscle-invasive bladder cancer (cT2N0), with fewer drawbacks than traditional chemotherapy. Although further studies are needed in support, this vision opens the opportunity for future clinical trials testing the potential incremental benefits of immunotherapy and the utility of novel biomarker- and imaging-based strategies to assess response to therapy.
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PMID:Neoadjuvant Chemotherapy or Immunotherapy for Clinical T2N0 Muscle-invasive Bladder Cancer: Time to Change the Paradigm? 3284 46