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Query: EC:2.7.10.1 (ERK)
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We have previously described a common region of deletion and allele loss on chromosome 17q in sporadic breast cancers that is likely to contain a tumor suppressor gene. The region, mapped to 17q12-q21, was bordered by D17S250 and D17S579 on the centromeric and telomeric sides, respectively. This deletion region overlaps the BRCA1 locus, which predisposes to familial breast and ovarian cancer. The most frequent loss of heterozygosity was observed at the thyroid hormone receptor alpha (THRA1) locus. Southern analysis revealed a rearrangement of THRA1 in the BT474 breast cancer cell line. This rearrangement represented a deletion of exons 8-10 of one THRA1 allele that was also coamplified with ERBB2. Northern blots showed two mutant transcripts in BT474 cells. Analysis of the mutant transcripts revealed fusion of the THRA1 exon 7 by splicing to a novel sequence designated BTR for "BT474 transcribed rearrangement." BTR was found to be highly conserved and mapped to 17q. The deletion in BT474 cells spans the entire BRCA1 region. To search for additional mutations in the THRA1 gene, all nine protein-encoding exons of THRA1 were examined for point mutations via single strand conformation analysis in a series of primary breast tumors, breast cancer cell lines, and lymphoblastoid cell lines derived from the youngest affected members of several German breast cancer families. No point mutations were detected, including the unrearranged THRA1 allele in BT474. We have thus excluded THRA1 as a commonly mutated sporadic breast cancer tumor suppressor gene and as the BRCA1 gene.
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PMID:Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a novel sequence on 17q in the BT474 cell line. 751 Oct 52

We examined the involvement of BRCA1, which plays a major role in Western breast cancer families, in Japanese breast cancer families. Eleven families, in which at least three individuals within third degree relatives were affected by breast cancer, were collected. Five of them were early-onset breast cancer families, in which the average age at diagnosis was less than 45 years, and the other six were late-onset families. Ovarian cancer was observed in one patient in the early-onset families. Using seven polymorphic markers on chromosome 17q21, D17S250, ERBB2, THRA1, D17S579, D17S588, GIP and NME1, linkage to BRCA1 was analyzed. Linkage was not detected in any single family. Assuming homogeneity in an inherited component that confines the susceptibility to breast cancer in all families, we summed the LOD scores of all families. The cumulative LOD score obtained was -1.86 for D17S588 at theta = 0.001, indicating no linkage with BRCA1. Since the proportion of families linked to BRCA1 is larger in Western early-onset breast cancer families than in late-onset ones, we also summed the LOD scores of five early-onset families. However, again a negative LOD score was obtained. These results suggest that BRCA1 is not a major breast cancer susceptibility gene in Japanese familial breast cancer.
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PMID:Linkage analysis of BRCA1 in Japanese breast cancer families. 785 87

Most cancers appear to be sporadic. However, 5 to 10% of cancers occur in genetically predisposed individuals. This inherited genetic risk is observed in syndromes such as familial polyendocrinopathies or phacomatosis such as neurofibromatosis, but also in familial aggregations of frequent cancers such as breast or colon cancers. Thanks to studies on molecular genetics, it has been possible over the last ten years to localize and to identify a large number of predisposing genes. These discoveries have permitted to better understand the biological basis of the predisposition and to offer counselling by identifying at-risk individuals in those families. In the case of multiple endocrine neoplasia type 2 associated with an elevated risk for medullary thyroid cancer, the gene involved is a protooncogene named RET and located on chromosome 10. Point mutations affecting specific regions of this gene are the basis of the genetic predisposition. For familial breast cancer, a susceptibility gene named BRCA1 has been located on the long arm of chromosome 17. Mutation of this gene (yet to be identified) led to very elevated risk of breast cancer and also in some families of ovarian cancer.
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PMID:[Genetic predisposition to cancer: familial forms of medullary thyroid cancer and breast cancer]. 803 90

To facilitate the positional cloning of the breast-ovarian cancer gene BRCA1, we constructed a high-density genetic map of the 8.3-cM interval between D17S250 and GIP on chromosome 17q12-q21. Markers were mapped by linkage in the CEPH and in extended kindreds in our breast cancer series. The map comprises 33 ordered polymorphisms, including 12 genes and 21 anonymous markers, yielding an average of one polymorphism every 250 kb. Twenty-five of the markers are PCR-based systems. The order of polymorphic genes and markers is cen-D17S250-D17S518-HER2-THRA1-RARA-D17S80 -KRT10-[D17S800-D17S857]-GAS- D17S856-EDH17B-D17S855-D17S859-D17S858-[++ +PPY-D17S78]-D17S183-EPB3-D17S579- D17S509-[D17S508-D17S190 = D17S810]-D17S791-[D17S181 = D17S806]-D17S797- HOX2B-GP3A-[D17S507 = GIP]-qter. BRCA1 lies in the middle of the interval, between THRA1 and D17S183. Markers from this map can be used to determine whether cancer is linked to BRCA1 in families, to evaluate whether tumors have lost heterozygosity at loci in the region, and to identify probes for characterizing chromosomal rearrangements from patients and from tumors.
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PMID:High-density genetic map of the BRCA1 region of chromosome 17q12-q21. 824 78

The chromosomal region 17q12-q21 contains a gene (BRCA1) conferring susceptibility to early-onset familial breast and ovarian cancer. An 8000-rad radiation-reduced hybrid (RH) panel was constructed to provide a resource for long-range mapping of this region. A large fraction of the hybrids (approximately 90%) retained detectable human chromosome 17 sequences. The complete panel of 76 hybrids was scored for the presence or absence of 22 markers from this chromosomal region, including 14 cloned genes, seven microsatellite repeats, and one anonymous DNA segment. Statistical analysis of the marker retention data employing multipoint methods provided both comprehensive and framework maps of this chromosomal region, including distance estimates between adjacent markers. The comprehensive RH map includes 17 loci and spans 179 cRays(8000). Likelihood ratios of at least 1000:1 support the 10-locus framework order: cen-D17S250-ERBB2-(THRA1, TOP2A)-D17S855-PPY-D17S190-MTBT1-GP3A++ +-BTR-D17S588-tel. The order obtained from RH mapping, when used in conjunction with other methods, will be useful in linkage analysis of breast cancer families and will facilitate the development of a physical map of this region.
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PMID:A radiation hybrid map of the BRCA1 region of chromosome 17q12-q21. 824 80

In order to pinpoint the locale of the gene for early-onset familial breast and ovarian cancer (BRCA1), polymorphisms were developed within the locus for thyroid hormone receptor alpha (THRA1) and for several anonymous sequences at chromosome 17q12-q21. The THRA1 polymorphism is a dinucleotide repeat with 10 alleles and heterozygosity.79. Gene mapping in extended families with inherited, early-onset breast and ovarian cancer indicates that BRCA1 is distal to THRA1 and proximal to D17S183 (SCG43), an interval of < 4 cM. This locale excludes HER2, THRA1, WNT3, HOX2, NGFR, PHB, COLIA1, NME1, and NME2 as candidates for BRCA1 but does not exclude RARA or EDH17B. Resolving the remaining recombination events in these families by new polymorphisms in the THRA1-D17S183 interval will facilitate positional cloning of the breast-ovarian cancer gene on chromosome 17q12-q21.
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PMID:THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. 846 Jun 37

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

Molecular genetic analysis of breast cancers indicates that the mechanisms underlying tumorigenesis are complicated. Many oncogenes and tumour suppressor genes have been implicated, encoding proteins that are important at many levels of cell regulation, from cell surface molecules responding to external signals (eg ERBB2) to nuclear factors controlling gene transcription (eg TP53, MYC). Several correlations have been found between certain genetic events and clinical outcome and have therefore proved useful prognostic indicators. The mapping and cloning of genes important in familial breast cancers (eg BRCA1) have provided the essential tools for pinpointing the genes that may be critical in early stage breast cancer as well as for developing genetic tests for predicting carrier status in breast cancer families. Clarification of the molecular consequences of mutation in breast cancer associated genes is beginning to address the factors that drive a normal breast cell to change into a breast cancer cell. However, these studies are still in their infancy, and considerable research will be required to complete the picture.
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PMID:Molecular genetics of sporadic and familial breast cancer. 871 25


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