Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.
 ...
PMID:Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. 882 21

Recently, genetic analyses in high risk families with several members suffering of breast and/or ovarian carcinoma led to the discovery of two genes, called BRCA1 and BRCA2, clearly responsible for hereditary predisposition of breast carcinoma. Another gene, p53, was also shown to be involved in hereditary predisposition of breast and other tumors in the setting of Li-Fraumeni syndrome. It is very important that women at risk could be seen by a specialized team for genetic counselling and explanation of advances and limits of molecular genetics. Such a team should be multidisciplinary in order to cover genetic, oncological, social, psychological and economical aspects of hereditary cancer predisposition. Prevention interventions and early detection methods are still investigational and definitely need to be performed in the setting of protocols in order to better evaluate their long term efficacy.
 ...
PMID:[Hereditary breast cancers]. 884 74

Numerous factors have been noted to be associated with risk of breast cancer. Indicators of endogenous hormonal alterations are among them: early age at menarche and late age at menopause, nulliparity, late age at first full term pregnancy and obesity in postmenopausal women. Other established risk factors are family history of breast cancer, histologic characteristics of benign tissue, mammographic patterns, exogenous hormones and alcohol consumption. Endogenous indicators may be a reflection of enhanced susceptibility, whereas exogenous exposures can have both independent effects on risk and the ability to interact with markers of inherited susceptibility. In case control studies of breast cancer, family history confers a risk elevation of two to three fold. The higher risk estimate occurs when first degree rather than second degree relatives are affected, or if more than one relative is affected. A relative diagnosed before age 45 increases risk for early-onset breast cancer. These findings have been obtained using either traditional analytic methods for case control data or an alternative strategy, which uses case control status as the predictor variable and models the risk to relatives in a time-dependent fashion. Risk of breast cancer is greater for the mother and sisters of cases than controls. The magnitude of risk increases with 1) decreasing age of diagnosis of the index case 2) additional family members with diagnosed breast cancer and 3) bilateral breast cancer in the index case. Although these two analytic approaches have somewhat different data requirements and may be subject to different biases, the results produced are quite consistent. Mutated p53 in female family members of patients with Li-Fraumeni syndrome was one of the first identified genetic susceptibility markers for breast cancer. Application of segregation and linkage analyses to pedigrees with multiple affected family members successfully focused the search for BRCA1. Recent cloning and sequencing of BRCA1 will allow for its use in risk assessment, diagnostic evaluation and screening of high risk women. BRCA1 appears to be primarily responsible for early-onset breast cancer in high risk families. Rare alleles of H-ras could account for some of the late-onset cases in unselected populations since at least 85% of breast cancer appears to be sporadic, other genetic markers yet to be identified undoubtedly exist.
 ...
PMID:Epidemiology of susceptibility to breast cancer. 889 88

Using a panel of ten polymorphic markers, we examined the frequency of loss of heterozygosity (LOH) on chromosome 17 in 55 sporadic ovarian tumours. LOH on 17p and 17q was observed to be 50% and 62% respectively. LOH at D17S5 was detected in 24/36 (67%) of malignant cases and in 19/43 (44%) at TP53; the marker D17S855 intragenic to the BRCA1 gene showed allele loss in 50% (20/40) cases. The data presented here suggest that loss of the whole chromosome 17 is a relatively frequent event (30%) in ovarian carcinomas and this observation is especially frequent for serous, transitional cell and anaplastic histological subtypes. Mucinous and endometrioid ovarian tumours showed only short interstitial deletions (4/11, 36%). The overall frequency of the short deletions was relatively low (7/43, 16%) in our panel of carcinomas. Amplification of c-erbB-2/neu oncogene was detected in 32% (11/34) of the carcinomas tested; the gene was amplified only in those histological subtypes in which high incidence of LOH on chromosome 17 was observed, and was associated with advanced stages of the disease. We conclude that different histological types of tumour may have different aetiological mechanisms, and tumour-suppressor genes on chromosome 17 might be associated specifically with serous and transitional cell ovarian carcinomas.
 ...
PMID:Allele loss from large regions of chromosome 17 is common only in certain histological subtypes of ovarian carcinomas. 893 40

The etiology of breast cancer involves a complex interplay of exogenous and endogenous factors, including genetic factors. The identification of oncogenes, tumor suppressor genes and human mismatch repair genes has helped to refine the characterization of breast carcinogenesis. The major types of genetic alterations in breast cancer are amplification of protooncogenes (ERBB2 and MYC) and DNA from chromosome band 11q13; mutation of p53; and loss of heterozygosity on 1p, 3p, 8p, 11p, 13q, 16q, 17p, 17q, 18q. The latter may imply inactivations of tumor suppressor genes. Recently, two distinct familial breast cancer susceptibility genes, BRCA1 and BRCA2, have been isolated. These findings enable to use these genes for genetic diagnosis in clinical oncology.
 ...
PMID:[Cytogenetic abnormalities, genetic alterations, and applications for genetic diagnosis in breast cancer]. 897 25

Familial breast cancer is characterized by young age at diagnosis, an increased risk of bilateral breast cancer, an increasing risk in conjunction with increasing numbers of affected family members, and a strong association with ovarian cancer. At least eight candidate breast cancer susceptibility genes have been identified. Mutations in BRCA1, BRCA2, p53, and the Cowden disease gene are relatively uncommon, are highly penetrant, and produce striking familial clusters of breast cancer. BRCA1 and BRCA2 are the most important of these, accounting for an estimated 80% of hereditary breast cancer and 5 to 6% of all breast cancers. Specific BRCA1 and BRCA2 mutations are of particular importance in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Mutations in the ataxia-telangiectasia gene and the rare HRAS1 variable number of tandem repeats polymorphisms are much more common but also much less penetrant. They do not produce dramatic familial aggregations of breast cancer but may prove to be responsible for a substantial proportion of all breast cancers if their epidemiologic association with breast cancer is confirmed. Predictive genetic testing for breast cancer risk is under way. Oncologists and primary-care physicians must become familiar with these genetic disorders and the issues surrounding predictive testing in order to make appropriate management decisions about women thought to have a high genetic risk of breast cancer.
 ...
PMID:Genetics of breast cancer. 900 88

Ovarian cancer has been described in association with three autosomal dominant syndromes: familial site-specific ovarian cancer, familial breast and ovarian cancer, and the hereditary nonpolyposis colon cancer syndrome. It appears that most breast-ovarian and site-specific ovarian cancer families are explained by mutations in the BRCA1 tumor suppressor gene. Other genes associated with inherited susceptibility to ovarian cancer include BRCA2, p53, and the DNA mismatch repair genes.
 ...
PMID:Hereditary ovarian cancer. 909 Apr 74

BRCA1 mutations, although implicated in disease predisposition in a major part of the hereditary breast cancer population, do not seem to be crucially involved in tumorigenesis of sporadic breast and ovarian cancers. This suggests that tumours arising in BRCA1 mutation carriers may differ from BRCA1 negative hereditary and sporadic cancer in genetic and biological features, as well as in clinical behaviour. Prior to BRCA1 analysis, 79 breast and 19 ovarian tumours from 57 breast and breast-ovarian cancer families, and 170 tumours from a comparison group of stage II breast cancers were studied with regard to histopathological features; immunohistochemistry [c-erbB-2, p53, oestrogen receptor (ER) and progesterone receptor (PR)], DNA flow cytometry and S-phase fraction. BRCA1 mutations were found in 40 breast and 15 ovarian tumours. The BRCA1 positive breast tumours were significantly more often of ductal type, histological grade III and manifested a heavy lymphocyte infiltration. Additionally, as compared to BRCA1 negative tumours, the BRCA1 positive tumours were significantly more often ER, PgR and c-erbB-2 negative. Furthermore, they were significantly more often DNA non-diploid, as well as being characterised by higher S-phase fraction values. These results suggest that BRCA1-induced breast cancers may manifest distinct tumour biological features of clinical importance.
 ...
PMID:Tumour biological features of BRCA1-induced breast and ovarian cancer. 915 18

The recent advances in the understanding of the pathogenesis of ovarian cancer have been helpful in addressing issues in diagnosis, prognosis and management. The study of ovarian tumours by novel techniques such as immunohistochemistry, fluorescent in situ hybridisation, comparative genomic hybridisation, polymerase chain reaction and new tumour markers have aided the evaluation and application of new concepts into clinical practice. The correlation of novel surrogate tumour specific features with response to treatment and outcome in patients has defined prognostic factors which may allow the future design of tailored therapy based on a molecular profile of the tumour. These have also been used to design new approaches to therapy such as antibody targeting and gene therapy. The delineation of roles of c-erbB2, c-fms and other novel receptor kinases in the pathogenesis of ovarian cancer has led initially to the development of anti-c-erbB2 monoclonal antibody therapy. The discovery of BRCA1 and BRCA2 genes will have an impact in the diagnosis and the prevention of familial ovarian cancer. The important role played by recessive genes such as p53 in cancer has raised the possibility of restoration of gene function by gene therapy. Although the pathological diagnosis of ovarian cancer is still confirmed principally on morphological features, addition of newer investigations will increasingly be useful in addressing difficult diagnostic problems. The increasingly rapid pace of discovery of genes important in disease, makes it imperative that the evaluation of their contribution in the pathogenesis of ovarian cancer is undertaken swiftly, thus improving the overall management of patients and their outcome.
 ...
PMID:Molecular approaches to diagnosis and management of ovarian cancer. 915 81

Aggregation of breast cancer in families is an established risk factor associated with increased incidence of the disease, which is a leading cause of morbidity and mortality among women in this country. Three genes have now been identified that confer increased susceptibility in families with a clear hereditary (i.e., Mendelian) pattern of expression: BRCA1, BRCA2 and p53. However, a significant number of women have an identified family history of breast cancer without clear Mendelian patterns of disease. Such patterns are consistent with the effect of more common genes with lower associated risk. Some evidence is available to implicate three additional genes that fit this category: AT, ESR and HRAS1. An area of active interest is genetically mediated variation in the metabolism of estrogens, a process controlled by several genes, each with more modest effects. The interaction of genes and environmental factors in breast cancer pathogenesis is of considerable public health importance.
 ...
PMID:Genetic factors in the pathogenesis of breast cancer: their role and relative importance. 916 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>