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)

p16MTS1/CDKN1 and the retinoblastoma protein Rb are both involved in negative regulation of G1/S progression in the mammalian cell cycle. Inactivation of one of these tumour suppressor genes is involved in many malignant tumours, and in some studies a negative correlation of p16 and Rb expression has been found. In order to study this interaction in endometrial carcinogenesis, we investigated 36 endometrial carcinomas, 11 cases of hyperplasia, 23 normal endometrial samples, and two uterine carcinoma cell lines by immunohistochemistry or RT-PCR. Rb was expressed in normal endometrial epithelium, hyperplasia, cell lines, and most carcinomas; negative immunostaining was only detected in 1 of 36 tumours. In contrast, p16 expression was weak in normal endometrium and increased in most cases of hyperplasia, but negative or minimally positive in 74% of the carcinomas and the Hec1B adenocarcinoma cell line, and there was no significant association with Rb immunostaining. Strikingly high p16 expression was found in foci of squamous metaplasia within hyperplastic or carcinomatous tissue. Deletion and mutation analysis of the p16 gene was performed in DNA from microdissected tumour samples and cell lines. No p16 deletion was found, and mutations were detected in only one tumour sample and Skut1B uterine mixed mesodermal tumour cells. Our data indicate that in spite of low or absent p16 expression, genetic alterations of the p16 and Rb tumour suppressor genes are rare in endometrial carcinogenesis.
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PMID:P16/MTS1 and pRB expression in endometrial carcinomas. 1007 Dec 31

In order to understand the origin of bladder cancer, very early urothelial lesions must be investigated in addition to more advanced tumors. Tissue from 31 biopsies of 12 patients with urothelial hyperplasias and simultaneous or consecutive superficial papillary tumors were used to microdissect urothelium from 15- microm sections of biopsies. The biopsies were obtained with the recently developed highly sensitive diagnostic method of 5-aminolevulinic acid-induced fluorescence endoscopy (AFE). Besides flat and papillary urothelial neoplasms, the method of photodynamic diagnostics also detects simple urothelial hyperplasias as fluorescent positive lesions. In addition, 12 fluorescence-positive biopsies showing histologically normal urothelium were investigated. Fluorescence in situ hybridization was done using a dual color staining technique of biotinylated centromeric probes of chromosomes 9 and 17 and digoxigenin-labeled gene-specific P1 probes for chromosomes 9q22 (FACC), 9p21(p16/CDKI2), and 17p13(p53). Ten of 14 hyperplasias (70%) showed deletions of chromosome 9. In 7 out of 8 patients with genetic alterations in the hyperplasias the genetic change was also present in the papillary tumor. Six out of 12 samples of microdissected normal urothelium also showed genetic alterations on chromosome 9. Microdissection of urothelial lesions, obtained during AFE, has led to the first unequivocal documentation of genetic changes in urothelial lesions diagnosed as normal in histopathology. Thus, this technical approach is important to provide insight into the earliest molecular alterations in bladder carcinogenesis.
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PMID:Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. 1007 49

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.
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PMID:Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. 1008 36

OBJECTIVE: To search for the minimal overlap region of tumor suppressor gene in laryngeal carcinoma and discuss the correlation of p16 gene with laryngeal carcinogenesis. METHODS: Five microsatellite polymorphism markers near p16 gene were selected to detect loss of heterozygosity (LOH) and microsatellite instability (MI) in 60 cases of laryngeal squamous cell carcinoma. RESULTS: The frequencies of LOH in 5 markers were less than 23.1%, while the frequencies of MI in 2 markers were higher, with the highest frequency (46.1%) in D9S1752. CONCLUSION: The results suggest that the deletion of p16 gene does not play an important role in the laryngeal carcinogenesis and there may exist a gene around D9S1752 participating in the development of laryngeal carcinoma, which correlates with the mutation of repair gene.
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PMID:[Loss of heterozygosity and microsatellite instability in laryngeal carcinoma near p16 gene] 1020 Mar 65

Alterations in cell proliferative activity are a common phenomenon in oral carcinogenesis. In this study, the expression of the cell cycle-associated proteins p16, pRb, p53, p27 and Ki-67 were examined by immunohistochemistry in precancerous and cancerous oral lesions, including verrucous carcinomas (VCs). Generally, expression of pRb, p53 and Ki-67 increased according to the cell proliferative activity or tumor progression, but p27 expression showed an inverse relationship. Comparing squamous cell carcinomas (SCCs) with VCs, there was a great difference in expression levels of p27, Ki-67 and p53, which seemed to reflect the different cell proliferative activities of these two tumors. Expression of p16 was low in both dysplasia and SCCs, whereas p16 expression was high in VCs. The high immunohistochemical expression for both p16 and pRb in VC is quite different compared with SCC, which may indicate a possible relationship between VC and human papillomavirus (HPV) infection.
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PMID:Immunohistochemical analysis of cell cycle-associated proteins p16, pRb, p53, p27 and Ki-67 in oral cancer and precancer with special reference to verrucous carcinomas. 1022 46

Normal somatic cells have a limited proliferative capacity in vitro: after a finite number of cell divisions they eventually enter a non-proliferative state referred to as senescence. Senescence is thought to be a major tumor suppressor mechanism, and many cancers contain cells that have escaped from senescence and become immortalized. The role of telomerase activation in immortalization is currently attracting considerable attention, but immortalization is often associated with other changes including loss of normal function of the tumor suppressor locus, INK4a/ARF. Two proteins, p16(INK4a) and p14(ARF), are encoded by this locus. Here we focus on p16(INK4a) and review accumulating evidence that loss of p16(INK4a) function may be involved in escape from the normal limits on cellular proliferative life span.
Carcinogenesis 1999 Jun
PMID:p16(INK4a) and the control of cellular proliferative life span. 1035 68

One of the most important components of G1 checkpoint is the retinoblastoma protein (pRB110). The activity of pRB is regulated by its phosphorylation, which is mediated by genes such as cyclin D1 and p16/MTS1. All three genes have been shown to be commonly altered in human malignancies. We have screened a panel of 26 oral squamous cell carcinomas (OSCC), nine premalignant and three normal oral tissue samples as well as eight established OSCC cell lines for mutations in the p16/MTS1 gene. The expression of p16/MTS1, cyclin D1 and pRB110 was also studied in the same panel. We have found p16/MTS1 gene alterations in 5/26 (19%) primary tumours and 6/8 (75%) cell lines. Two primary tumours and five OSCC cell lines had p16/MTS1 point mutations and another three primary and one OSCC cell line contained partial gene deletions. Six of seven p16/MTS1 point mutations resulted in termination codons and the remaining mutation caused a frameshift. Western blot analysis showed absence of p16/MTS1 expression in 18/26 (69%) OSCC, 7/9 (78%) premalignant lesions and 8/8 cell lines. One cell line, H314, contained a frameshift mutation possibly resulting in a truncated p16/MTS1 protein. pRB was detected in 14/25 (56%) of OSCC but only 11/14 (78%) of these contained all or some hypophosphorylated (active) pRB. In premalignant samples, 6/8 (75%) displayed pRB, and all three normal samples and eight cell lines analysed contained RB protein. p16/MTS1 protein was undetectable in 10/11 (91%) OSCCs with positive pRB. Overexpression of cyclin D1 was observed in 9/22 (41%) OSCC, 3/9 (33%) premalignant and 8/8 (100%) of OSCC cell lines. Our data suggest p16/MTS1 mutations and loss of expression to be very common in oral cancer cell lines and less frequent in primary OSCC tumours. A different pattern of p16/MTS1 mutations was observed in OSCC compared to other cancers with all the detected p16/MTS1 mutations resulting in premature termination codons or a frameshift. The RB protein was expressed in about half (44%) of OSCCs and its expression inversely correlated with p16/MTS1 expression. In conclusion, we show that abnormalities of the RB pathway are a common mechanism of oral carcinogenesis.
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PMID:Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines. 1038 82

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogenesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in >40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15INK4B and p16INK4A were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/ sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.
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PMID:High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. 1039 89

Abnormalities of several oncogenes and tumor suppressor genes have been identified in carcinomas of the pancreas during the last decade, and multiple genetic changes have been demonstrated in individual carcinomas. The variety of genetic changes suggests that multiple etiologic factors contribute to carcinogenesis in the pancreas. Several of these changes are characteristically found in specific types of tumors, suggesting that different causes and molecular mechanisms are involved. One example is the loss of heterozygosity at the von Hippel-Lindau (VHL) gene locus in both wild type and hereditary serous cystadenomas, and another is the virtual absence of K-ras mutation and p53 abnormalities in acinar cell carcinomas, whereas both are frequently found in ductal adenocarcinomas. Multiple lines of evidence place K-ras mutation very early and loss of p53 and p16 as late events during ductal cell carcinogenesis. The timing and order of other genetic changes such as loss of the DPC4 tumor suppressor function is less certain.
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PMID:Molecular pathology of invasive carcinoma. 1041 52

To date, only a limited number of tumor suppressor genes have been identified as being inactivated in lung cancer. The p53 and RB genes are frequently inactivated by genetic alterations such as chromosomal deletions and loss-of-function mutations, while the p16 gene is inactivated not only by genetic alterations but also by transcriptional silencing due to hypermethylation. Recently, it was shown that the FHIT gene encompassing the chromosomal fragile site, FRA3B, is also inactivated in a large proportion of lung cancers. Several lines of evidence indicate the presence of additional tumor suppressor genes involved in lung carcinogenesis. Lung cancer cells often show deletions at multiple chromosomal regions, and deletion mapping studies have defined more than 30 regions dispersed on 21 different chromosome arms as candidate tumor suppressor loci. Several chromosomal regions hypermethylated in lung cancer cells and a number of chromosomal fragile sites have been mapped to the regions deleted in lung cancer. These chromosomal loci can harbor unknown tumor suppressor genes inactivated in lung cancer. Studies on the inherited susceptibility to lung cancer in mice have also indicated the presence of additional tumor suppressor genes for lung cancer. Further analyses of these loci should elucidate how many tumor suppressor genes are involved in human lung carcinogenesis. Molecular and functional analyses of those genes will make it possible to fully understand the molecular mechanism of lung carcinogenesis.
Carcinogenesis 1999 Aug
PMID:How many tumor suppressor genes are involved in human lung carcinogenesis? 1042 84


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