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)

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen-BRCA1-SSTR2-D17S2058-D17S929-D17S722-+ ++D17S937-D17S802-tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24-proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors.
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PMID:Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: implications for tumorigenesis. 972 14

A series of 25 primary prostate cancers in Japanese were screened for loss of heterozygosity and microsatellite instability using twelve microsatellite markers containing APC, DCC, TP53, BRCA1, and BRCA2. Frequent loss of heterozygosity was observed for D8S201 (48%), LPL (48%), and DCC (26%). In contrast, the incidence did not exceed 15% at BRCA1 and BRCA2 loci. Microsatellite instability was observed in 28% of stage B, C, and D cancers. These data suggest that microsatellite instability and loss of unidentified genes on chromosome 8p may be involved in carcinogenesis of the prostate; however, BRCA1 and BRCA2 may not be largely involved in the development of prostate cancer in the Japanese population.
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PMID:Allelic loss and microsatellite instability in prostate cancers in Japan. 977 25

The ovarian carcinogenesis is not well known because the diagnosis is usually delayed to an advanced stage with a lot of chromosomic abnormalities. On the other hand, there is a lack of animal models and preneoplastic patterns are discussed. Different ways of studying are in progress. Prophylactic oophorectomy in women with BRCA1 mutation provides ovaries that can be compared to a control group. Epithelial or stromal changes are observed in the familial risk group more frequently than in the controls and could be preneoplastic. An experimental approach has been developed in order to confirm the Fathalla's theory of the incessant ovulation by culturing cells of rat surface ovarian epithelium with a high proliferative pressure. These cells become malignant in 10 out of 30 cases (after 10 cultures). The transformed tumor cells are a syngeneic tumor model that can be transplanted in the animal and analysed by molecular biology technics. This allowed to show the loss of a potentially tumor suppressor gene, lot 1, in the transformed cells and on the other hand the overexpression of a gene coding for a protease enzyme the cathepsin B, which is a marker of an aggressive metastatic power.
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PMID:[Natural history of ovarian adenocarcinomas: from epidemiology to experimentation]. 986 87

Germ-line alterations of BRCA1 are responsible for about 50% of familial breast cancers. Although its biological function(s) has not yet been fully determined, it has been suggested that it may act as a tumor suppressor gene in breast and ovarian cancers. In sporadic breast cancers alterations of BRCA1 have not been detected and in vitro experiments have indicated that BRCA1 negatively regulates cellular proliferation. The present study was designed to identify and quantify, the BRCA1 mRNA levels, in normal and neoplasic human breast tissue. BRCA1 mRNA molecules were quantified using competitive reverse transcriptase PCR assays. DNA methylation patterns of this gene have been analysed by Southern blot experiments using methylation sensitive restriction enzymes. We found that BRCA1 mRNA levels were significantly lower in sporadic breast cancers (37 cases analysed, 24 cases of invasive ductal carcinomas not otherwise specified (NOS), two lobular carcinomas in situ two medullary carcinomas, four invasive lobular carcinomas, two invasive mucinous carcinomas and three invasive ductal carcinomas with predominantly in situ component) compared with normal breast tissues (P=0.0003). This down-regulation of BRCA1 is observed in all histologic types analysed. In invasive ductal carcinomas NOS, this down-regulation does not correlate with any of the prognostic factors studied (tumor size, node status, histologic grade, hormone receptor status). In the samples analysed, alterations of DNA methylation patterns were not dectected in the vicinity of the major transcription start site. These data suggest the involvement of BRCA1 in the carcinogenesis of these histologic types.
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PMID:Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. 987 32

Present prospects of breast cancer prevention are being developed in three main areas: (a) genetics, to understand the real importance of familial breast cancer and genetic testing; (b) lifestyle, to study various risk factors, including delayed first pregnancies and smaller number of pregnancies, and months of breast feeding; (c) chemoprevention, to identify chemical agents potentially able to inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells. Different target populations for breast cancer chemoprevention may be recognized. Primary chemoprevention may involve a wide population of healthy women with a moderate risk due to nonpenetrant genetic factors (e.g., one first-degree relative with breast cancer) or exposure to known promoting agents (e.g., hormone replacement therapy). A second level of primary chemoprevention may involve a limited population at very high risk because of highly penetrating genetic predisposition to cancer (e.g., BRCA1 mutation carriers). Secondary chemoprevention may involve subjects with premalignant or early malignant lesions, e.g., breast atypical hyperplasia and carcinoma in situ or microinvasive disease. Prevention trials using clinical endpoints are always subject to high costs. Also, the risk of unexpected detrimental effects has recently been high-lighted, and much emphasis has been put on the search for intermediate, surrogate endpoints. Surrogate endpoints are biological markers that may be assessed or observed prior to the clinical appearance of the disease, bearing some relationship to the development of that disease. They are referred to as intermediate since they occur some time between a given intervention that affected the disease process and the time of the clinical diagnosis of the disease. The use of surrogate endpoint biomarkers in pivotal cancer chemoprevention trials may lead to a rational choice of agents which are likely to affect cancer incidence in subsequent phase III trials.
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PMID:Prevention of breast cancer: focus on chemoprevention. 992 43

The activation of oncogenes and the inactivation of tumour suppressor genes play a critical role in laryngeal tumorigenesis. Recent investigations revealed that 8p, 9p and 17q arms of human chromosomes harbour tumour suppressor genes (TSGs) such as p16 and BRCA1 with an important role in the multistage carcinogenesis of the larynx. In order to investigate the implication of these novel TSGs in the development of laryngeal neoplasia we performed a loss of heterozygosity (LOH) analysis using a bank of 15 polymorphic microsatellite markers (4 at 8p21, 7 at 9p21 arm and 4 at 17q arm surrounding the BRCA1 region) in a series of 32 cytological specimens (19 squamous cell carcinoma, 13 benign lesions of the larynx). Both benign and malignant specimens exhibited genetic alterations with at least one microsatellite marker. Fifteen (47%) out of the 32 specimens exhibited LOH at 8p21, 25/32 (78%) showed LOH at 9p21 and 18/32 (56%) displayed LOH at 17q21. Genetic alterations were detected in both benign and malignant lesions for all the loci tested suggesting an important role of these regions in the development of laryngeal neoplasia. This is the first report of detection of microsatellite alterations not only in solid tumours of the larynx but in laryngeal cytological specimens, suggesting that microsatellite analysis may be a useful tool in the primary diagnosis of the disease.
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PMID:Loss of heterozygosity at 8p, 9p and 17q in laryngeal cytological specimens. 993 Mar 65

The observation that normal pathways of differentiation and development are invariably altered during the process of carcinogenesis implies an intrinsic relationship between these processes. This relationship is particularly evident in the breast, as exemplified by the existence of endocrine risk factors for breast cancer that are related to the timing of normal developmental events. Understanding the mechanisms by which normal developmental events alter breast cancer risk is a central focus of our laboratory. Herein, we describe three approaches being taken in our laboratory toward defining the molecular basis of this relationship. These include: determining the roles played by the tumor suppressor genes, BRCA1 and BRCA2, in the normal differentiation and development of the breast; studying the function of three novel protein kinases identified in our laboratory in mammary epithelial development; and defining the molecular and cellular changes that occur in the breast as a result of reproductive events known to influence breast cancer risk.
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PMID:Mammary gland development, reproductive history, and breast cancer risk. 1019 94

The genetic determinants for most breast cancer cases remain elusive. However, a mutation in a tumor suppressor gene, such as p53, BRCA1, BRCA2, or ATM, has been determined to be one mechanism of breast carcinogenesis. It has been established that inherited mutations in p53, BRCA1, and BRCA2 significantly contribute to breast cancer risk, although the importance of an inherited ATM mutation is controversial. Sporadic mutations in p53 are also common in breast cancer cells. The precise deficiencies that result from these genetic mutations have yet to be fully described. Although the functions of these genes are different, they are all involved in the maintenance of genomic stability after DNA damage. Mutations that impair the function of these four genes may adversely affect the manner in which DNA damage is processed. It is likely that the risk of breast cancer development is increased through this mechanism. In this article, we review the relevancy of p53, BRCA1, BRCA2, and ATM mutations to breast cancer development, and review the in vitro, in vivo, and clinical data exploring the mechanisms by which these mutations affect genomic integrity and DNA damage repair.
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PMID:Tumor suppressor genes and breast cancer. 1033 46

The rat is an extremely valuable model for studies of inherited susceptibility to breast cancer because the characteristics of rat mammary cancer and human breast cancer are so similar. There are now several rat models for studying sensitivity versus resistance, or cell autonomy versus non-cell-autonomy, for spontaneous and induced mammary cancers. It is known that the tumor-resistant Cop [20, 21] and WKy [8] strains carry dominant resistance genes that inhibit both spontaneous and induced mammary tumors. The WF and SD strains are known to carry dominant sensitivity genes that appear to increase susceptibility to induced but not spontaneous mammary tumors. The presence of both resistance and sensitivity genes in the Cop strain is intriguing, and provides a unique model for studying the interactions of both types of genes. It appears that the resistance genes together are at least partially dominant over the sensitivity gene in this model since the F1 rats develop only a few tumors. Yet another strain, the F344, has an intermediate sensitivity and has been shown to carry neither sensitivity or resistance genes. Thus, all these models and data indicate that sensitivity genes are not necessary for the development of mammary tumors, and neither are they sufficient. However, loss of resistance gene function is necessary but is not sufficient for mammary tumor development. Studies have shown that the sensitivity and resistance genes act directly within the mammary epithelial cells rather than globally in the rat. The products of these genes also do not appear to act at early steps in the carcinogenic process because there have been no observed effects of these genes on carcinogen metabolism or DNA adduct formation. It would appear that these genes act at later stages of mammary carcinogenesis. Identification and isolation of these genes should aid our understanding of the inherited components of human breast cancer. With the increasing availability of genetic markers and large-insert libraries for the rat genome, genetic and physical mapping studies are now a reality for the genes involved in mammary carcinogenesis of the rat. Such studies have already revealed the multigenic nature of this cancer, supporting the idea that the limited penetrance of BRCA1 and BRCA2 in human breast cancer is due to loci that modify the effects of the sensitivity genes. Assuming that human homologues of the Mcs genes exist, cloning the genes and defining the human homologues may provide a way to identify the risk for breast cancer development in women. Analysis of the function of such genes may also lead to the development of new drugs for chemoprevention and/or therapy of this lethal disease.
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PMID:The genetic components of susceptibility to breast cancer in the rat. 1037 59

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian cancer syndrome. To clarify the possible involvement of the BRCA1 protein in mammary carcinogenesis in sporadic and hereditary forms, we have analyzed the BRCA1 protein expression pattern in five breast epithelial cell lines, including a BRCA1-deficient cell line, and 162 breast cancer tissue samples [including 108 sporadic, 35 hereditary (BRCA1 status unknown), and 19 BRCA1-associated cases] from Japanese women. Twelve anti-BRCA1 antibodies were tested by fixation conditions, in which nuclear localization of BRCA1 protein was preserved, and by specificity of the antibodies, which was evaluated in BRCA1-deficient cancer cells. Using monoclonal antibodies applicable to immunohistochemical analysis of paraffin-embedded tissue sections, we found high-level expression of BRCA1 protein in normal mammary epithelium and various degrees of reduced expression in breast cancer cells. Of the 19 BRCA1-associated breast cancer tissues, 15 (79%) showed reduction (8 cases) or complete loss (7 cases) of nuclear expression. Thirty (28%) of 108 sporadic and 6 (17%) of 35 hereditary carcinomas showed reduced BRCA1 protein expression. Reduction of BRCA1 protein expression in sporadic carcinomas was associated with solid-tubular phenotype, with poor tubular differentiation, and with an overexpression of c-erbB-2 protein, which is one of the prognostic factors in breast cancer. Our data suggest that reduced expression of BRCA1 protein may play an important role in mammary carcinogenesis, not only in BRCA1-associated breast carcinomas, but also in sporadic carcinomas, and also suggest that mechanisms other than mutation may be involved in its reduced expression.
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PMID:Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases. 1038 7


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