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 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of breast cancer involves a complex interplay of various factors, including genetic alterations. Many studies have been devoted to the identification and characterization of mutations that occur frequently during breast tumorigenesis. The major types of genetic abnormalities that are frequently observed in breast tumors are amplification of protooncogenes (MYC, ERBB2) and DNA from chromosome band 11q13; mutation of TP53; and loss of heterozygosity from chromosomes and chromosome arms 1, 3p, 6q, 7q, 8p, 11, 13q, 16q, 17, 18q, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, linkage analyses of large families with a predisposition to breast cancer have been performed in order to map breast cancer susceptibility genes (TP53, BRCA1, BRCA2). The findings have thrown light on the molecular mechanisms of breast cancer and have enabled various genetic markers to be used in clinical oncology.
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PMID:Genetic alterations in breast cancer. 860 12

The recent remarkable progress in molecular biology has revealed that various kinds of genetic alteration occur in cancers. Recently, many genes that cause hereditary cancer have been identified. For example, hMSH2 and hMLH1, which are known as DNA mismatch repair genes have been found to cause HNPCC (hereditary non-poliposis colorectal cancer). Mutation of RET oncogene has been recognized in the families of MEN (multiple endocrine neoplasia) type II. Mutations of the tumor suppressor genes are the most common changes in the genes of familial cancer. BRCA1 and BRCA2 are tumor suppressor genes that have recently been identified as familial breast and ovarian cancer, familial breast cancer genes. This paper reviewed the hereditary cancer families in which genetic alterations have been revealed and the recent progress in mapping and cloning of familial breast cancer candidate genes which have not been identified.
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PMID:[Familial cancer and oncogenic factors]. 867 87

Human carcinomas are generally considered to develop through the accumulation of various genetic abnormalities. The major types of genetic alterations that are frequently observed in breast cancer are amplification of protooncogenes (MYC, ERBB2); mutation of TP53; and loss of heterozygosity on chromosomes 1, 3p, 8p, 11p, 13q, 17q, 17, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, two major distinct breast susptibility genes were isolated, namely BRCA1 and BRCA2. We performed PCR-SSCP analysis to determine the role of the BRCA1 gene in Japanese breast cancer and investigated how multiple genetic alterations contribute to tumor development and/or progression in primary breast cancer, using a large number of tumor materials.
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PMID:[Genetic alterations and DNA-based diagnosis in breast cancer]. 870 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.
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PMID:[Cytogenetic abnormalities, genetic alterations, and applications for genetic diagnosis in breast cancer]. 897 25

In the last two decades, molecular studies have enlightened the complexity of the genetic alterations that occur in breast cancer cells. To date, more than 40 different genes or loci have been found to be altered in breast carcinomas. Although some of these genes, as for example ERBB2, appear to be mutated in a high proportion of cases, their mechanism of action and their role in the different stages of cancer development are still poorly understood. More recently, two major determinants of the inherited predisposition to breast cancer, BRCA1 and BRCA2, have been isolated. As a consequence, it is now possible to screen families with a positive history of breast carcinomas for the identification of mutations carriers, in order to address these individuals into adequate programs of cancer surveillance and prevention.
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PMID:Molecular genetics of breast cancer. 927 27

To characterize the biological features of breast cancer associated with germ-line mutations in BRCA1 and BRCA2, invasive tumors were studied from 58 Jewish women ascertained through studies of early-onset breast cancer. All women were tested for the BRCA1 founder mutations 187delAG (commonly known as 185delAG) and 5385insC (commonly known as 5382insC) and the BRCA2 founder mutation 6174delT. Mutations were detected in 17 of 58 (29.3%) women. Comparing BRCA-associated breast cancers (BABCs) to cases arising in women without founder mutations, no differences were noted in tumor size, tumor stage, or frequency of axillary nodal involvement. Infiltrating ductal carcinoma was the predominant histological type in both groups. BABCs were significantly more likely to be of histological grade III (100 versus 63%; P = 0.04), estrogen receptor negative (75 versus 35%; P = 0.004), and HER2/neu negative (87 versus 58%; P = 0.04). An associated intraductal component was present in 59% of BABCs and 76% of cancers not associated with mutations (P = not significant). A high Ki-67 labeling index was more commonly observed in BABCs than in cases without mutations (83 versus 48%; P = 0.09). There were no differences between the two groups in the frequency of expression of epidermal growth factor receptor, cathepsin D, bcl-2, p27, p53, or cyclin D. There were no significant differences in relapse-free or overall survival. These observations suggest that breast cancers arising in Jewish women with germ-line BRCA founder mutations have a greater proliferative potential than cancers in women without such mutations. Additional studies of BABC are required to determine the nature and implications of additional genetic abnormalities occurring in these tumors.
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PMID:BRCA-associated breast cancer: absence of a characteristic immunophenotype. 958 22

Alu elements comprise >10% of the human genome. We have used a computational biology approach to analyze the human genomic DNA sequence databases to determine the impact of gene conversion on the sequence diversity of recently integrated Alu elements and to identify Alu elements that were potentially retroposition competent. We analyzed 269 Alu Ya5 elements and identified 23 members of a new Alu subfamily termed Ya5a2 with an estimated copy number of 35 members, including the de novo Alu insertion in the NF1 gene. Our analysis of Alu elements containing one to four (Ya1-Ya4) of the Ya5 subfamily-specific mutations suggests that gene conversion contributed as much as 10%-20% of the variation between recently integrated Alu elements. In addition, analysis of the middle A-rich region of the different Alu Ya5 members indicates a tendency toward expansion of this region and subsequent generation of simple sequence repeats. Mining the databases for putative retroposition-competent elements that share 100% nucleotide identity to the previously reported de novo Alu insertions linked to human diseases resulted in the retrieval of 13 exact matches to the NF1 Alu repeat, three to the Alu element in BRCA2, and one to the Alu element in FGFR2 (Apert syndrome). Transient transfections of the potential source gene for the Apert's Alu with its endogenous flanking genomic sequences demonstrated the transcriptional and presumptive transpositional competency of the element.
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PMID:Potential gene conversion and source genes for recently integrated Alu elements. 1104 48

Hepatocellular carcinoma (HCC) is the most frequently occurring liver carcinoma world-wide. Clinical and molecular medical analyses have produced a considerable amount of information about liver carcinogenesis. Loss of heterozygosity (LOH) analyses have revealed several chromosomal loci harboring potential tumor suppressors. These data support the idea that deletion or inactivation of tumor suppressors including RB, p53, BRCA2, E-cadherin and other candidate genes seem to be common events in HCC development. Factors associated with cell cycle regulation via the Wnt- and MAPK/ERK signaling pathways are frequently deregulated in hepatocarcinogenesis. Aberrant activation of telomerase also occurs in precancerous as well as cancerous lesions in HCC patients. To characterize the wide variety of genetic events that occur in HCC, mRNA expression has been compared in HCC and non-cancerous liver tissues, and several differentially expressed genes have been identified. Hepatitis B and C viruses are the main risk factors for HCC, and indeed some accessory functions of viral products seem to contribute to tumor development; however, whether they have a direct carcinogenic effect has not yet been established.
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PMID:Genetic and epigenetic events in human hepatocarcinogenesis. 1135 Dec 62

Based largely on studies of cell lines in vitro and of transgenic mouse models, disruptions of transforming growth factor (TGF) beta signaling are thought to contribute to the development and progression of human breast cancer. However, whether and how TGF-beta signaling becomes disrupted during human breast cancer development in vivo remains largely unknown. To address this question, we have compared the patterns of expression and activation of the postreceptor components of the TGF-beta signaling pathway, the so-called Smads, in human breast cancer cell lines with those in breast carcinoma specimens. None of the breast carcinoma cell lines were growth arrested by TGF-beta in vitro. Each of the tumor cell lines expressed normal levels of Smad2 and -3. Moreover, TGF-beta treatment induced phosphorylation of Smad2 (Smad2P) in each of these lines, except those that lacked TGF-beta type II receptors. Moreover, only one of the cell lines failed to express Smad4. Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, Smad2P, as well as Smad4, indicating their ability to proliferate within a microenvironment that contains bioactive TGF-beta. Thirty cases (6.6%) failed to express Smad2P, suggesting the loss of TGF-beta receptor signaling. Nine cases (2%) failed to express Smad4, and 3 of these also failed to express Smad2P. Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression. Loss of Smad signaling was not associated with any particular histological subtype, histological or nuclear grade, estrogen- or progesterone receptor expression, or HER2/neu expression. Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases. Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival. Finally, analysis of a small cohort of hereditary breast cancers failed to reveal any association between BRCA1 or BRCA2 genotype and alterations in Smad signaling.
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PMID:Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. 1180 1

This review is focused on genetic factors that may influence the development and/or appearance of breast cancer metastases. Over the last decade there have been significant advances in the understanding of genetic predisposition to breast cancer. The first breast cancer predisposing gene to be identified was TP53, and this was followed over the next 5 years by two more genes, BRCA1 and BRCA2, which from a population perspective are much more important than TP53. Other rarer genes have subsequently been identified, but the role of more common, less penetrant genes in breast cancer susceptibility remains unknown. Recent work has shown that breast cancers occurring in women carrying germ-line BRCA1 mutations tend to have clinicopathological features that are usually associated with a poor prognosis, such as high grade, estrogen receptor negative status and somatic TP53 mutations. On the other hand, they are usually ERBB2 negative. Whether or not such tumors are more or less likely to metastasize, and hence be associated with a poor outcome, is currently uncertain and has been the subject of much debate. Here, we outline some of the clinicopathological features of hereditary breast cancer, discuss the prognostic studies that have been performed, and introduce some possible new research directions.
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PMID:The contribution of inherited factors to the clinicopathological features and behavior of breast cancer. 1201 34


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