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Biomedical subjects

M Emi

Publications and source records attributed to M Emi.

At least 91 records · Page 5Linked to original sources
PubMed1999

Frequent multiplication of chromosomal region 8q24.1 associated with aggressive histologic types of breast cancers.

Carcinogenesis is considered to be a multi-step process that may involve cumulative genetic alterations. One such alteration, gain of chromosomal material, has the potential for activating genes that promote carcinogenesis in breast tissues. Using 14 polymorphic microsatellite markers on the long arm of chromosome 8 (8q), we examined 142 sporadic breast cancers for abnormalities in the copy-numbers of these loci. At each locus examined, a 2- to 3-fold increase in intensities of bands representing single alleles was observed in 57 (40%) of the tumors, indicating that 'multiplication' of the DNA sequence had occurred on 8q. A 16-cM region on 8q24.1 was commonly multiplied among the tumors with partial multiplications. Multiplication on 8q24.1 was observed more frequently in invasive solid-tubular or scirrhous tumors (48/92, 52%) than in less aggressive histologic types (7/25, 28%, P = 0.031). Thus, multiplication of tumor-promoting gene(s) located on 8q24.1 may play a role in the development and/or progression of a substantial proportion of primary breast cancers, particularly those of the invasive histology.

Alleles↗
PubMed1999

Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1.

BACKGROUND: Frequent allelic losses on the short arm of chromosome 8 in several types of human cancers, and deletion maps of this region in tumor DNAs, have suggested that 8p harbors one or more genes that are important for suppressing tumorigenesis in the tissues in question. METHODS: To define the locations of potential tumor suppressor genes involved in breast carcinoma, the authors examined 144 primary breast carcinomas for loss of heterozygosity at 18 highly polymorphic microsatellite loci on 8p. They also sought correlations between allelic loss on 8p and several clinicopathologic parameters. RESULTS: Allelic loss was observed in 74 of the 144 sporadic breast carcinomas examined. Whereas more than half of the informative tumors showed loss of an allele at every locus on the short arm, 32 showed partial or interstitial deletions. Deletion mapping in this panel of tumors identified two distinct commonly deleted regions, one in a 1-cM interval flanked by D8S511 and D8S1991 at 8p22-p23.1, and the other in a 16-cM interval flanked by D8S136 and D8S1477 at 8p22-p21. Allelic losses in both of these regions were observed more frequently in tumors of the solid-tubular or scirrhous type than in less aggressive histologic types. Furthermore, allelic loss in either region occurred more frequently in larger and infiltrative tumors (T1 < T2 < T3). CONCLUSIONS: The association of allelic losses on 8p with advanced tumor stage and aggressive histologic type implies that loss or inactivation of one of at least two putative tumor suppressor genes on 8p may contribute to the progression of breast carcinoma.

Breast Neoplasms↗
PubMed1999

Frequent allelic loss at the TOC locus on 17q25.1 in primary breast cancers.

Sporadic breast cancers often show allelic losses on the long arm of chromosome 17. Since the BRCA1 gene lies at 17q21.1 and the TOC locus, associated with esophageal cancer, lies at 17q25.1, either gene could be the target of those losses. We examined both loci in 178 primary breast cancers, using microsatellite markers covering the relevant regions of 17q, and observed allelic losses in 97 tumors (55%). Losses were most frequent at markers around the TOC locus (48% at D7S1839 and 43% at D17S1603), where we identified a distinct commonly deleted region within a I -cM interval. Another larger, separate commonly deleted region including the BRCA1 gene was also identified, which exhibited 45% of allelic loss (at D17S934). Allelic loss on 17q was more frequent in tumors of the solid-tubular histologic type (P = 0.0129) and in estrogen-negative and progesterone-negative tumors (P = 0.0281 and 0.0196, respectively). The results indicated that BRCA1 and TOC are independent targets of allelic loss on 17q in primary breast cancers, and that inactivation of the TOC locus in particular may play an important role in the genesis of sporadic breast tumors.

BRCA1 Protein↗
PubMed1999

Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22.

To identify the location of one or more putative tumor suppressor genes that may be involved in urinary bladder cancer, we examined 82 such tumors for allelic losses at 19 microsatellite loci on 8p. Loss of heterozygosity was observed in 31 of the cases. Deletion mapping identified a commonly deleted region at 8p22, within the 1-Mb interval flanked by D8S1135 and AFM177XB10. Allelic loss at 8p22 was associated with higher tumor grade (17/31, 55%, vs. 12/51, 23%; P = 0.0013). Furthermore, no tumor that retained heterozygosity for markers at 8p22 had metastasized to distant organs, whereas a substantial portion of tumors that lost alleles in that region had done so (0/51, 0%, vs. 6/31, 20%; P = 0.001). These data imply that loss or inactivation of tumor-suppressing activity encoded on 8p contributes to malignancy and to the metastatic potential of bladder cancers.

Chromosome Deletion↗
PubMed1999

Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma.

In papillary thyroid carcinomas, the genes for receptor-type tyrosine kinase, RET or TRKA, are sometimes rearranged, resulting in fusion of its tyrosine kinase domain to 5' portions of several activating genes. In a papillary thyroid carcinoma, we identified a novel gene (ELKS), the 5' portion of which is fused to the RET gene by gene rearrangement due to the translocation t(10;12)(q11;p13). Subsequent cloning of the ELKS cDNA revealed that ELKS encodes a novel 948 amino acid peptide and is expressed ubiquitously in human tissues. The presence of multiple coiled-coil domains in the ELKS product suggests that the ELKS protein forms dimers. Since the tyrosine kinase of RET is activated by dimerization that occurs when its ligands bind to the receptor, fusion of RET with the 5' dimerization domains of ELKS would activate its cytoplasmic tyrosine kinase constitutively in papillary thyroid carcinomas.

Amino Acid Sequence↗
PubMed1999

Ethnic difference in contribution of Sp1 site variation of COLIA1 gene in genetic predisposition to osteoporosis.

Osteoporosis, a condition characterized by low bone mineral density (BMD) leading to bone fragility [1], is a major public health concern in Japan as well as in other countries. Although genetic predisposition seems to be a factor in the pathogenesis of osteoporosis [2-4], the precise cohort of genes that may be involved is not well defined. The COLIA1 and COLIA2 genes encode polypeptide constituents of collagen type Ialpha1 and Ialpha2, respectively. Both are important candidates as genetic regulators of BMD, since mutations in either gene result in osteogenesis imperfecta, a disorder characterized by severe osteoporosis [5]. Some patients with adult osteoporosis also carry mutations in COLIA1 or COLIA2 genes [6].http://link.springer-ny. com/link/service/journals/00223/bibs/65n5p352.html</++ +hea

Aged↗
PubMed1999

Linkage of interleukin 6 locus to human osteopenia by sibling pair analysis.

Osteopenia and osteoporosis are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlations between levels of bone mass and a number of genetic factors. The genes involved could regulate metabolism, formation and resorption of bone, all processes that determine bone mass. We tested 192 sibling pairs of adult Japanese women from 136 families for genetic linkage between osteopenia and allelic variants of four candidate genes (interleukin-6, interleukin-6 receptor, calcium-sensing receptor, and matrix gla protein) using qualitative and quantitative methods, and using as genetic markers dinucleotide-repeat polymorphisms present in or near each of those loci. The interleukin-6 locus showed evidence of linkage to osteopenia analyzed as a qualitative trait, with mean allele sharing of 0.40 (P=0.0001) in discordant pairs and 0.55 (P=0.04) in concordant affected pairs. Variation at this locus was also linked to decreased bone mineral density measured as a quantitative trait (P=0.02). Analyses limited only to the post-menopausal women showed similar or even stronger results. No other locus among those tested showed any evidence of linkage by either method. The results provided strong evidence that genetic variation at the interleukin-6 locus affects regulation of bone mineral metabolism and confers risk for osteopenia and osteoporosis in adult women.

Adult↗
PubMed1999

Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan.

Rearrangements of the RET and TRK proto-oncogenes, which generate fusion oncogenes, are frequent in papillary thyroid carcinomas in Caucasian populations. To determine the spectrum of gene rearrangements in Japanese patients, we systematically examined 40 papillary thyroid carcinomas for all possible types of gene fusion events involving RET or TRK genes. RET rearrangements were found in ten tumors (25%): ret/PTC1 had occurred in two tumors, ret/PTC2 in one, ret/PTC3 in six, and a novel RET rearrangement in the remaining patient. In this last patient, the 5' novel sequence was fused in-frame to the RET amino acid sequence; thus, the fusion gene may encode a protein with a RET kinase domain at the carboxy terminus. The RET gene was fused to 5' donor sequences at the beginning of exon 12 in all ten tumors. No rearrangements involving the TRK gene were found in this panel of carcinomas. Our results indicated that constitutive activation of the RET by gene rearrangement is a frequent mechanism of papillary thyroid carcinogenesis in Japanese adults.

Adult↗
PubMed1999

Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the human nuclear factor kappa-beta subunit 1 (NFKB1) locus.

The transcriptional factor nuclear factor kappa-beta (NFKB) consists of a multicomponent protein complex that plays a major role in the regulation of many viral and cellular genes. The NFKB complex has two alternative DNA binding subunits. We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the NFKB subunit 1 (NFKB1) gene located at 4q23-24. High heterozygosity (0.813) makes this polymorphism a useful marker in the genetic study of disorders affecting the immune response and cell differentiation.

Base Sequence↗
PubMed1999

Association of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenopausal Japanese women.

Twin studies have shown strong correlations between bone mass and genetic factors. Some of the genes involved could regulate bone metabolism and bone formation and resorption, all processes that determine bone mass. One candidate gene, interleukin 6 (IL-6), has been implicated in the pathogenesis of bone loss because it stimulates osteoclasts. We investigated a possible association between the CA repeat polymorphism at the IL-6 gene locus and the bone mineral density (BMD) of radial bone in 472 postmenopausal Japanese women. Genotypes were classified into six groups according to the number of CA repeats present, from 13 to 18. BMD was expressed as adjusted BMD, which was the body mass index (BMI)- and age-adjusted average BMD. The 73 women who possessed an A1 allele (134 bp, containing 18 repeats of CA) had significantly lower adjusted BMD than those participants (n = 399) who did not carry an allele of that size (mean +/- SD values, 0.294 +/- 0.064 vs 0.312 +/- 0.061 g/cm2; P = 0.0221). This result suggests that genetic variation at the IL-6 gene locus is associated with some determinants of BMD in postmenopausal women.

Adenine Nucleotides↗
PubMed1999

Association of diffuse panbronchiolitis with microsatellite polymorphism of the human interleukin 8 (IL-8) gene.

Diffuse panbronchiolitis (DPB) is a distinctive chronic inflammatory lung disease predominantly found in Asian populations. Although its etiology is unknown, DPB is considered to be a multifactorial disease of whose susceptibility is determined by genetic predisposition unique to Asians. We and others have previously reported that the B*5401 allele of the human leukocyte antigen (HLA)-B gene or a closely linked gene in the HLA region on 6p21.3 is one of the major genetic factors in susceptibility to this disease. However, the association with B*5401 is not absolute and the contribution of other genetic or environmental factors should also be considered. Here, four candidate genes that are postulated to play a role in the pathophysiology of DPB, namely, RON-kinase, CYP3A4, motilin, and interleukin (IL)-8, were chosen, and association studies between microsatellite markers at these loci and DPB were conducted. We demonstrated the presence of a specific allele at the IL-8 locus was associated with the disease (c2 = 9.13; P = 0.0025; corrected P [Pc] < 0.05). Although further studies are needed to examine whether neutrophil accumulation in the airways of patients with DPB is controlled by a possible genetic variation of IL-8 or other chemokine genes located in the region 4q12-q13, our data suggest that genes other than those of the HLA system may also contribute to a genetic predisposition to DPB.

Asian People↗
PubMed1999

Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the SREBP cleavage-activating protein (SCAP) locus.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in animal cells. A polymorphic dinucleotide (CA) repeat sequence was isolated from a genomic clone containing the SCAP gene and was mapped to chromosome 3p21.3. High heterozygosity (0.89) makes this polymorphism a useful marker in the genetic study of disorders affecting lipid metabolism.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Two single nucleotide polymorphisms of the hSNF5/INI1 gene.

We found two single nucleotide polymorphisms at the hSNF5/INI1 gene located on 22q11.2, encoding a member of the chromatin-remodelling SWI/SNF multiprotein complexes. A guanine/adenine polymorphism at codon 299 in exon 7, and another guanine/adenine polymorphism at 39 bp upstream of exon 9 were identified. As the gene was recently identified as a tumor suppressor gene for malignant rhabdoid tumor, this polymorphism may be useful for the genetic study of susceptibility for human malignancies of various tissue origins.

Adenine↗
PubMed1999

A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.

Adult↗
PubMed1999

Genomic structure and chromosomal mapping of the human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) gene.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in mammalian cells. The entire genomic structure of the human SCAP gene was cloned in a 110-kb region covered by overlapping genomic clones. The SCAP gene was localized to chromosome 3p21.3 by fluorescence in situ hybridization. The human SCAP gene is over 30 kb in length and contains 23 exons and 22 introns. The transcription initiation site within exon 1 is separate from the initiation codon coded in exon 2. Analysis of exon/intron structure revealed that the gene consists of a mosaic of exons encoding functional protein domains. Exon 1 encodes the 5' non-coding region. Exons 2, 3, 7, 8, 9, 10, 11, 13, and 15, respectively, encode each of the eight transmembrane regions. Of these, exons 7-11 encode the sterol-sensing domain. Exons 15-23 encode the hydrophilic carboxyl-terminal domains containing four copies of a motif called the Trp-Asp (WD) repeats that interact with and regulate SREBP and the site-1 protease. Sequence analysis of the 5'-flanking region showed that it comprised a high G/C-rich region and contained adipocyte determination and differentiation-dependent factor 1 (ADD1)/SREBP-1 binding sites in addition to Sp1 and AP2 sites. This suggests that SCAP gene expression is under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism. Our data establish the basis of investigation for molecular variants in this gene that may result in alterations in plasma lipoprotein levels and/or derangement of intracellular lipid metabolism.

Base Sequence↗
PubMed1999

A common Ile796Val polymorphism of the human SREBP cleavage-activating protein (SCAP) gene.

We identified a new common amino acid polymorphism of isoleucine/valine at codon 796 in exon 16 of the gene for human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), a central regulator of lipid synthesis and metabolism in animal cells. It can be detected as an MslI restriction fragment length polymorphism. The allelic frequencies were: isoleucine (A) allele, 0.57 and valine (G) allele, 0.43. This polymorphism may be useful for genetic studies of disorders affecting intracellular lipid metabolism and hyperlipidemia.

Humans↗
PubMed1999

Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

Loss of heterozygosity (LOH) of loci on chromosome 18q occurs in a majority of colorectal cancers. The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS). The gene product functions as a cytoplasmic mediator in the signaling pathway of transforming growth factor beta (TGF-beta). To investigate the potential role of DPC4/SMAD4 gene in colorectal cancers, we examined 73 tumors of clinical stages II or III from Japanese patients, for LOH at 18q21 and also for subtle mutations anywhere within the coding region of DPC4/SMAD4. LOH was identified in 50 (78%) of the 64 tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in seven of those tumors: two frameshift mutations, a 1-bp deletion (326 del T) in exon 8 and a 1-bp insertion (50-51 ins A) in exon 1; two nonsense mutations, Arg445Ter in exon 10 and Glu538Ter in exon 11; and three missense mutations, Asn129Lys in exon 2, Tyr95Asn in exon 2, and Asp355Glu in exon 8. Three of the seven mutations were observed in the mad homology 1 (MH1) domain encoded by exons 1 and 2. In all of the tumors carrying intragenic mutations of one allele, LOH analysis had shown that the other allele was missing. The results demonstrated that inactivation of both alleles of the DPC4/SMAD4 gene occurs in a substantial proportion of advanced colorectal cancers, and that the DPC4/SMAD4 gene probably exerts a tumor-suppressor effect for colorectal carcinogenesis that fulfills the criterion of the two-hit concept proposed by Knudson [A.G. Knudson, Hereditary cancer, oncogenes, and anti-oncogenes, Cancer Res. 45 (1985) 1437-1443.].

Alleles↗