Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
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PMID:Cyclin D1 in breast cancer. 1006 68

Investigation of early breast carcinogenesis is limited by the difficulty in obtaining cell cultures or adequate fresh frozen material and by the fact that available data from in situ techniques are interpreted in terms of various classification systems. Our studies in a series of pure ductal carcinomas in situ (DCIS) were conducted in accordance with the recommendations of the international Consensus Conference (Hum. Pathol., 28, 122-125, 1997) relative to processing, determination of lesion extent, and histological stratification primarily on nuclear grade (NG). A multifactorial study performed in 15 low- and 16 high-NG DCIS (68% detected by mammography) included the following: (1) morphological analysis of NG, necrosis, and architectural pattern; (2) detection of numerical genomic abnormalities at ERBB2, MYC, CCND1, Xq1.2 and 20q13 loci by fluorescence in situ hybridization on interphase nuclei; and (3) immunohistochemical determination of cell proliferation, p53 accumulation, hormonal receptors and bcl-2 expression on serial sections of formalin-fixed, paraffin-embedded specimens. High NG, comedo/solid pattern and necrosis were significantly associated with amplification at one or more loci, the number of amplified loci, amplification at the ERBB2 locus, absence of bcl-2 and hormonal receptor expression and high cell proliferation (p < 0.05). High NG and comedo/solid pattern were significantly associated with MYC amplification and p53 accumulation, and necrosis with CCND1 amplification (the only gene amplification detected in low NG DCIS). These data provide additional information on the early steps of breast carcinogenesis, in accordance with currently recognized criteria of histological classification.
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PMID:Gene amplifications detected by fluorescence in situ hybridization in pure intraductal breast carcinomas: relation to morphology, cell proliferation and expression of breast cancer-related genes. 1100 1

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.
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PMID:Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. 1128 83

To identify amplified oncogenes involved in hepatocellular carcinomas (HCC), we applied a genomic DNA microarray spotted with 57 oncogenes to 20 HCCs. Aberrations in DNA copy number also were analyzed by comparative genomic hybridization (CGH) using an aliquot of DNA samples. In 5 of 20 HCCs, only 6 oncogenes (CCND1, FGF3/FGF4, SAS/CDK4, TERC, MET, and MYC) were amplified, whereas in the remaining 15 tumors no oncogenes were amplified. A comparison of DNA microarray and conventional CGH analyses showed that, although 5 of 6 amplified oncogenes shown by microarray were located in chromosomal regions shown by CGH to have increased DNA copy numbers, not all genes located in such chromosomal regions were affected. One of the amplified oncogenes (SAS/CDK4) was found in a chromosomal region that was undetected by CGH. We, therefore, conclude that amplification of the oncogenes examined in this series is not directly implicated in hepatocellular carcinogenesis.
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PMID:Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis. 1167 33

Mouse mammary tumor virus (MMTV) is a retrovirus, activating Wnt genes (Wnt1/int-1, Wnt3/int-4, Wnt10b), Fgf genes (Fgf3/int-2, Fgf4, Fgf8) and other genes (Notch4/int-3, Eif3s6/int-6) due to proviral integration. Among 19 WNT genes, WNT3 and WNT14B genes are clustered in human chromosome 17q21, WNT3A and WNT14 in human chromosome 1q42, WNT10A and WNT6 in human chromosome 2q35, and WNT10B and WNT1 in human chromosome 12q13. Among 22 FGF genes, FGF19, FGF4 and FGF3 genes are clustered in human chromosome 11q13, while FGF23 and FGF6 in human chromosome 12p13. WNT and FGF gene clusters are conserved between the human genome and the mouse genome. Activation of mouse Wnt or Fgf genes due to proviral integration of MMTV occurs in 5 out of 13 clustered genes, and in 1 out of 28 solitary genes (p=0.0033), which clearly indicates that mouse Wnt or Fgf gene clusters are recombination hot spots associated with carcinogenesis. Recombination results in retroviral integration as well as in chromosomal translocation, gene amplification and deletion during carcinogenesis. The CCND1-FGF19-FGF4-FGF3 gene cluster in human chromosome 11q13 is amplified in breast cancer, squamous cell carcinoma of head and neck, and bladder tumors, and is also translocated in parathyroid tumors and B-cell lymphoma. WNT gene clusters on human chromosome 1q42, 2q35, 12q13, and 17q21 as well as FGF gene cluster on human chromosome 12p13 might be amplified or translocated in human cancer just like FGF gene cluster on human chromosome 11q13.
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PMID:WNT and FGF gene clusters (review). 1242 77

Bladder cancer is the most common urinary tumors in China. Carcinogenesis of bladder is a multistep process. Accumulation of abnormal genotypes in a long period leads to malignant phenotypes. The genes associated with bladder carcinogenesis include oncogenes (such as H-ras, FGFR3, erbB2, CCND1, mdm2), tumor suppressor genes (such as INK4A/ARF, Rb, TP53, PTEN, TSC1, PTCH, DBCCR1), and DNA mismatch repair genes, etc. In this review, the authors discussed the recent research advances on the genes associated with bladder carcinoma.
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PMID:[Research advances on bladder cancer associated genes]. 1256 47

The CCND1-ORAOV1-FGF19-FGF4-FGF3-FLJ10261-FADD-PPFIA1-EMS1 locus on human chromosome 11q13 is frequently amplified in esophageal cancer, breast cancer, and bladder tumors. FGF19, FGF4 and FGF3 genes are implicated in embryogenesis and carcinogenesis. We proposed in 2002 the hypothesis that mouse Fgf15 might be the ortholog of human FGF19 based on comparative genomics. Here, we identified zebrafish fgf19 and oraov1 genes by using bioinformatics to demonstrate the hypothesis. Zebrafish fgf19 gene, consisting of three exons, was located around nucleotide position 121802-124963 of zebrafish genome draft sequence AL929586.12 in the reverse orientation. Zebrafish fgf19 (209 aa) was more homologous to chicken fgf19 and human FGF19 than to rodent Fgf15. Zebrafish oraov1 gene, consisting of five exons, was located around nucleotide position 112172-115838 of AL929586.12 in the reverse orientation. Zebrafish oraov1 protein (141 aa) was more homologous to human ORAOV1 than to rodent Oraov1. The CCND1-ORAOV1-FGF19-FGF4 locus was well conserved between human and zebrafish genomes in the order of genes, in the direction of genes, and in the exon-intron structure. Rat Ccnd1-Oraov1-Fgf15-Fgf4 locus was synthenic to mouse Ccnd1-Oraov1 (also known as 2210010N10Rik)-Fgf15-Fgf4 locus. Fgf15, homologous to human FGF19 and zebrafish fgf19, was located on the synthenic locus of human FGF19 and zebrafish fgf19 within rodent genomes. Based on the evolutionary conservation of the CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human, it was concluded that Fgf15 gene is the rodent ortholog of human FGF19 gene.
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PMID:Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. 1279 7

Expression of cyclin D1 is believed to lead to progression through the G1-S cell cycle checkpoint, and both experimental and pathological evidence suggest that over-expression of this protein may increase the risk of several cancers, including transition cell carcinoma of the bladder. Two major transcripts have been described for CCND1, the gene encoding cyclin D1. CCND1 870A-->G, a common single nucleotide polymorphism in the splice donor region of exon 4, may modulate expression of these transcripts, with the A variant resulting in an increased pool of the isozyme encoded by transcript form b. A statistically significant 1.8-fold increased risk for bladder cancer among individuals possessing the A/A genotype was recently reported in a hospital-based case-control study conducted among native Japanese. We conducted a population-based case-control study of incidence of bladder cancer among non-Hispanic whites in Los Angeles County to examine the relationship between CCND1 870A-->G genotypes and bladder cancer risk. No association between the A/A genotype and risk was observed (odds ratio = 0.90, 95% confidence interval 0.60-1.33). The null association was not appreciably modified by bladder cancer risk factors, including lifetime smoking history, or by histopathologic classification.
Carcinogenesis 2003 Oct
PMID:A case-control study of cyclin D1 CCND1 870A-->G polymorphism and bladder cancer. 1289 8

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
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PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1943 86

For genomewide monitoring and identification of biomarkers of head and neck squamous cell carcinoma (HNSCC), we have conducted a systematic characterization of gene expression profiles, using human cDNA microarrays containing 9K clones, in 25 HNSCC cell lines and 1 immortalized human oral keratinocyte cell line. We used normal human oral keratinocytes (NHOKs) as a reference. Our study showed that genes primarily involved in cell cycle regulation, oncogenesis, cell proliferation, differentiation, apoptosis and cell adhesion were widely altered in the 26 cell lines. Upregulated genes included known oncogenes, protein kinases, DNA-binding proteins and cell cycle regulators, while those commonly downregulated included differentiation markers, cell adhesion proteins, extracellular matrix proteins, structural proteins (keratins) and protease inhibitor proteins. Compared to NHOK, we observed a striking reduction in the expression of genes involved in terminal differentiation, suggesting that a loss in this process is an important signature of HNSCC. In addition, hierarchical clustering analysis as well as principal component analysis revealed 2 distinctive subtypes of gene expression patterns among the 26 cell lines, reflecting a degree of heterogeneity in HNSCC. By applying significance analysis of microarrays, 128 genes were selected for being distinctively expressed between the 2 groups. Genes differentially expressed in the 2 subgroups include cell proliferation-related genes, IGFBP6, EGFR and VEGFC; tumor suppression and apoptosis-related genes such as Tp53, Tp63; as well as cell cycle regulators such as CCND1 and CCND2 (cyclins D1 and D2), suggesting that the 2 subgroups might have undergone different pathways of carcinogenesis.
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PMID:Global gene expression profiles of human head and neck squamous carcinoma cell lines. 1535 37


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