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

The B6C3F1 mouse is used worldwide to gauge the carcinogenic hazard posed by chemicals to humans. An assessment of the ability of this rodent model to predict human neoplasia requires an evaluation of similarities and differences in the genetics of tumor formation between these two species. We examined 142 spontaneous and chemically-induced liver tumors isolated from the B6C3F1 mouse for losses of heterozygosity (LOH) at 78 polymorphic loci and compared these results to genetic changes known to occur in human hepatocellular carcinoma. Approximately a third of the 142 mouse tumors exhibited LOH, suggesting that tumor suppressor gene inactivation may be involved in the formation of mouse liver tumors. Most of the LOH observed was restricted to seven chromosome sites and most of the tumors that underwent LOH lost alleles from only one of those seven sites. The relatively few losses seen in these mouse tumors distinguished them from clinical stage human tumors in that, in the mouse tumors, interstitial deletions appeared more frequently than losses of whole chromosomes. Only four mouse tumors lost a whole chromosome. LOH occurred at loci of the mouse genome syntenic to areas of the human genome known to harbor the Wilms', retinoblastoma, APC, MCC and DCC tumor suppressor genes; these genes have never been associated with hepatocellular carcinomas. Losses observed on chromosomes 5 and 8 (syntenic to human chromosomes 4 and 16) suggest tumor suppressor genes that are common to hepatocellular carcinomas from both species, while losses on chromosome 9 suggest involvement of a previously unidentified tumor suppressor gene.
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PMID:Loss of heterozygosity in spontaneous and chemically induced tumors of the B6C3F1 mouse. 805 44

Knowledge of the patterns of allelic loss has been useful in identifying the spectrum of the tumor suppressor genes involved in various tumor types. Such analyses in pancreatic carcinoma have been difficult due to the characteristic host desmoplastic reaction to the neoplasm. We have assembled the first allelotype of pancreatic adenocarcinoma, a survey for allelic loss among each chromosomal arm, using seven cryostat-dissected neoplasms. The fractional allelic loss in these seven neoplasms was 0.18, a value similar to that seen previously in colorectal carcinoma. Alleles of chromosome 18q (lost in five of six informative tumors) and of chromosome 17p (lost in four of five informative tumors) were commonly affected. Neither APC mutations (33 neoplasms), allelic shifts of dinucleotide repeats (26 neoplasms), nor immunohistochemical evidence of retinoblastoma protein underexpression (7 neoplasms) were found. Further evaluation of allelic loss in pancreatic cancer would benefit from improved methods for the analysis of lost genetic material which overcome the problems posed by the high admixture of nonneoplastic stromal and inflammatory cells in these tumors.
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PMID:Allelotype of pancreatic adenocarcinoma. 816 8

The recent advances in molecular biology have led to a concept that carcinomas arise from the accumulation of a series of genetic alterations involving activation of protooncogenes and inactivation of tumor suppressor genes. The present study was designed to elucidate that such processes take place in the tumorigenesis of the uterine endometrium as well. The incidence of ras gene mutation, which were mostly composed of the point mutations of k-ras codons 12 and 13, was higher in carcinomas (31%) than atypical hyperplasias (15%), with marginal significance, but has not been associated with aggressiveness of the carcinomas. Thus, k-ras activations may occur as an early event in tumorigenesis. Mutations of tumor suppressor gene, p53, were detected in 24% of carcinomas and 8% of atypical hyperplasia, while they are not statistically different. The p53 mutations were associated with poorly differentiated adenocarcinomas. The most common pattern of the base change detected in endometrial carcinomas was the transition from G:C to A:T. The p53 mutations at CpG sites were frequent, especially at codon 248. Loss of heterozygosity (LOH) was more frequently detected than the mutations and most cases with LOH harbored the mutations, suggesting that allelic loss may precede the mutation in the tumorigenesis of endometrium. Expression of p53 was well correlated with type of the p53 mutation and its overexpression is associated with aggressive clinical behavior, suggesting the possible application of p53 as a prognostic indicator. The other tumor suppressor genes, Retinoblastoma gene (RB) and DCC gene, were also involved in the endometrial carcinogenesis. LOH and abnormal m-RNA of RB were detected in 15% and 33% of carcinomas, respectively, and associated with advanced clinical stage and poorly differentiated adenocarcinomas. LOH of DCC was also detected in some cases while that of APC was not detected. Thus, tumor suppressor genes may also play an important role as later events in carcinogenesis by inactivation mechanism consisting of the loss of one chromosomal allele and/or mutation of the gene in the remaining allele. Human papillomavirus (HPV) DNA type 16 was curiously detected in 5% of cases by both Southern blot and in situ hybridization analyses. Consequently, two third of endometrial carcinomas examined in the present study for ras, p53, RB, DCC, APC and HPV showed abnormality of at least one of these genes. The abnormality of multiple genes may contribute as an etiologic role to multisteps in carcinogenesis of the endometrium.
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PMID:[Genetic alterations and transformations in development and establishment of uterine endometrial carcinomas]. 837 Oct 6

Two distinct gene classes have been implicated in colorectal carcinogenesis. Tumour promoter genes (oncogenes, dominant oncogenes) produce an excessive positive stimulus to cell proliferation. The ras family of oncogenes are an example. Acquired mutations of the c-k-ras gene are commonly found in colonic adenomas and carcinomas. Tumour suppressor genes (anti-oncogenes, recessive oncogenes) normally constrain or regulate cell proliferation. Loss of this function through gene deletion or mutation is oncogenic. Inherited tumour suppressor gene mutations have now been identified in several of the familial cancer syndromes. Acquired tumour suppressor gene mutations are found in both sporadic and hereditary cancers. Together with the tumour promoter genes they provide the genetic basis for the cellular changes occurring during carcinogenesis. The retinoblastoma gene was the first human tumour suppressor gene to be characterized and exemplifies the class. More recently, linkage studies in the hereditary cancer syndromes and the detection of specific deletions in sporadic tumours have helped to identify several new tumour suppressor genes. At least four of these (MCC, APC, p53 and DCC) apparently contribute to sporadic colorectal carcinogenesis. Germ line APC mutations produce the inherited colorectal cancer syndrome familial adenomatous polyposis (FAP). Detection of these mutations using linked markers has already found clinical application in the screening of families with this disease. In the future, genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) and the recognition of those genetically susceptible to sporadic colorectal cancer may become possible. At the same time, as our understanding of the genes involved improves, new avenues for treatment and prevention of colorectal cancer may emerge.
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PMID:Tumour suppressor genes and colorectal neoplasia. 847 56

According to a "two-hit" model, dominantly inherited predisposition to cancer entails a germline mutation, while tumorigenesis requires a second, somatic, mutation. Non-hereditary cancer of the same type requires the same two hits, but both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both copies of the RB1 tumor-suppressor gene in both hereditary and non-hereditary forms. In fact, most dominantly inherited cancers show this relationship. New dominantly inherited cancers show this relationship. New questions have arisen, however. When a tumor-suppressor gene is ubiquitously expressed, why is there any specificity of tumor predilection? In some instances, it is clear that two hits produce only a benign precursor lesion and that other genetic events are necessary. As the number of necessary events increase, the impact of the germline mutation diminishes. The number of events is least for embryonal tumors, and relatively small for certain sarcomas. Stem-cell proliferation evidently plays a key role early in carcinogenesis. In some tissues it is physiological, as in embryonic development and in certain tissues in adolescence. In adult renewal tissues, the sites of the common carcinomas, mutation may be necessary to impair the control of switching between renewal and replicative cell divisions; the APC gene may be the target of such a mutation.
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PMID:Hereditary cancer: two hits revisited. 860 60

Identification of inherited cancer-predisposing genes offers opportunities for cancer prevention. Inherited susceptibility genes have been identified, primarily through studies of unusual cancer cases and families but also through general population studies. Examples include the RB1 gene for retinoblastoma; the WT1 gene for Wilms' tumor; germline p53 mutations in families with the Li-Fraumeni syndrome; the NF1 and NF2 genes for neuroblastomatosis, types 1 and 2; the VHL gene for renal cancer and other tumors associated with Von Hippel-Lindau disease; the APC gene for adenomatous polyposis coli; the BRCA1 gene for hereditary breast and ovarian cancer; and the mismatch repair genes for colon and other common cancers. For some cancers, identification of gene carriers might be beneficial for targeting screening and chemopreventive interventions. On the other hand, predisposition testing for cancer has the potential for harm from loss of insurability and employability, psychological distress, social stigmatization and other adverse effects. Research is needed to identify predisposition testing procedures that maximize benefits while minimizing harm to subjects. Chemoprevention trials in genetically susceptible populations offer the prospect of finding effective methods of reducing future cancer risk.
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PMID:Identification and management of inherited cancer susceptibility. 874 2

Familial cancers associated with genetic background are of the most intensively investigated diseases in recent years. The phenotype is apparent with most of these diseases and can easily be traced through family history. Induction in familial cancer appears, on current evidence, to be not different from that observed in sporadic cancer. The first suppressor gene Rb gene was cloned from retinoblastoma. There are two representative hereditary colorectal cancers: familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). The gene responsible for FAP (APC gene) was cloned in 1991. The APC gene is a negative regulator of beta-catenin and is considered to play the role of gatekeeper in the adenoma carcinoma sequence. Thereafter a group of genes, human homologues of mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2, hMSH6), have been identified as the genes responsible for HNPCC. These are called care taker genes, which serve to maintain genetic stability. Therefore, if one of those genes undergoes mutation, the rate of mutation increases significantly. It has only been in the last 20 years that familial cancer has become an important issue. In association with such advances, predictive testing can now be performed on at risk persons. Persons at risk can thus be accurately counseled and screened for early detection of disease.
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PMID:[Familial cancer: recent advances]. 1041 Jan 40

Hepatocellular carcinoma (HCC) is linked etiologically to viruses (hepatitis B virus [HBV] and hepatitis C virus [HCV]), chemical carcinogens (i.e., aflatoxins), and other environmental and host factors causing chronic liver injury. Some hepatoblastomas may be linked to inherited gene mutations, but adult hereditary HCC appears to be rare. HCCs display gross genomic alterations, including DNA rearrangements associated with HBV DNA integration, loss of heterozygosity, and, less importantly, chromosomal amplifications and loss of imprinting. Many genes with somatic mutations have now been identified in these tumors. Most frequently involved genes are tumor suppressor genes such as p53, M6P/IGF2R, beta-catenin, p16INK4A, and retinoblastoma genes. Most identified mutations are somatic, but germline mutations of p16INK4A, APC, and BRCA2 have also been reported. Oncogenic activation of several cellular genes such as cyclin D and cyclin A have been described in HCC, but the possible implication of candidate viral oncogenes (i.e., X protein of HBV) is still debated. A comprehensive analysis of all the genetic changes described for HCC demonstrates that at least four different growth regulatory pathways are altered in these tumors. However, each pathway appears to be implicated in a limited fraction of these tumors, suggesting that HCCs are genetically heterogenous neoplasms. This genetic heterogeneity correlates with the heterogeneity of etiologic factors implicated in HCC.
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PMID:Genetic aspects of hepatocellular carcinogenesis. 1051 3

Pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor type 1 (PAC(1)) signaling and desensitization were investigated in human retinoblastoma Y-79 cells. Concentration-dependent stimulation of cAMP accumulation was observed in Y-79 cells incubated for 30 min with PACAP38, PACAP27, or VIP (10(-12) to 10(-6) M). The following EC(50) values were calculated: PACAP38, 24+/-3 pM; PACAP27, 99+/-8 pM; and VIP, 29+/-3 nM. Homologous desensitization of PAC(1) receptors in Y-79 cells pretreated with 10 nM PACAP38 or PACAP27 for 60 min was characterized by a 30-50% reduction in PACAP-stimulated cAMP accumulation (p<0.0001) and a two- to fivefold rightward shift in EC(50) values (p<0.0001). PAC(1) receptor desensitization was not accompanied by a reduction in PAC(1) mRNA expression. We concluded that the desensitizing effect of PACAP38 was homologous because neither corticotropin-releasing factor- nor (-)-isoproterenol-stimulated cAMP accumulation was altered by PACAP38 preincubation. Pretreating Y-79 cells with the protein kinase A (PKA) inhibitor H89 failed to inhibit homologous PAC(1) receptor desensitization. Similarly, pretreating Y-79 cells with the protein kinase C (PKC) inhibitors staurosporine or bisindolylmaleimide failed to alter homologous PAC(1) receptor desensitization. Although activation of PKA by dibutyryl cAMP or forskolin did not desensitize PAC(1) receptors, direct activation of PKC by PMA heterologously desensitized PAC(1) receptors, reducing cAMP accumulation 34.2+/-2.2% (p<0.001). Using RT-PCR, mRNA levels for G-protein-coupled receptor kinase 3 (GRK3), but not GRK2, were found to increase 2.2- to 4.8-fold in Y-79 cells exposed to PACAP38 for 10 min to 24 h (p<0.001). PAC(1) receptor desensitization decreased 72.5+/-4.3% (p<0.001) in Y-79 cells transfected with a GRK3 antisense cDNA construct that also reduced GRK3 protein expression 48.5+/-7.9% (p<0.0005). These experiments demonstrate that GRK3 plays an important role in the homologous desensitization of retinoblastoma PAC(1) receptors, whereas PKC, but not PKA, contributes to the heterologous desensitization of retinoblastoma PAC(1) receptors.
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PMID:G-protein-coupled receptor kinase 3- and protein kinase C-mediated desensitization of the PACAP receptor type 1 in human Y-79 retinoblastoma cells. 1116 32

This review focuses on the functional role and structural features of the genes involved in common hereditary cancers. Most of these tumors are sporadic and the genetic alterations responsible for their genesis take place over several cell generations; nevertheless, 5 to 10% of the human tumors are hereditary, with a rapid development. Cancer susceptibility genes have been classified as "gatekeepers" (e.g. RB1, ki-ras) and "caretakers" (e.g. hMLH1 and hMSH2, BRCA1). The first step in identifying individuals at high risk of developing a specific inherited form of cancer, and who should therefore undergo genetic tests, is the detailed construction of family history (an accurate cancer family history that includes at least three generation pedigrees, an appropriate cancer risk assessment and an effective genetic counseling). At present, the most useful methods of risk assessment are those performed on the following genes: BRCA1 and BRCA2 especially for hereditary breast and ovarian cancer, hMLH1 and hMSH2 for hereditary non polyposis colorectal cancer, APC for familial adenomatous polyposis, ret for medullary thyroid carcinoma, p53 for the Li-Fraumeni syndrome, p16 for melanoma and RB1 for retinoblastoma. In conclusion, the development of new diagnostic tests will permit a more accurate assessment of risk in individuals who have not so far shown any sign or symptom of the disease.
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PMID:Hereditary common cancers: molecular and clinical genetics. 1120 30


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