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M Emi

Publications and source records attributed to M Emi.

At least 145 records · Page 8Linked to original sources
PubMed1998

Familial hypercholesterolemia kindred in Utah with novel C54S mutations of the LDL receptor gene.

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 determine the genetic etiology of the lipoprotein abnormalities, we screened DNA samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a T-to-A transversion at nucleotide position 223, causing substitution of Ser for Cys at codon 54 in exon 3 of the receptor gene. This amino acid replacement would disrupt one of the disulfide bonds necessary for maintenance of the secondary structure of the repeat at the N-terminal of the receptor, prevent correct folding of the receptor, and result in defective intracellular transport of the receptor.

Adult↗
PubMed1998

Familial hypercholesterolemia with cholesteryl ester transfer protein deficiency.

A 21-year-old male was clinically diagnosed with familial hypercholesterolemia (FH) by the manifestations of hypercholesterolemia, tendon xanthoma and family history of premature coronary heart disease. Low density lipoprotein receptor gene was analyzed in attempt to determine a possible point mutation. The normal sequence was partially preserved, and the patient was genetically diagnosed as a heterozygote of FH. In addition, screening for two cholesteryl ester transfer protein (CETP) gene mutations common to Japanese revealed the patient to be a heterozygote of CETP deficiency. A complication of two influential mutations for atherosclerotic ailments was genetically ascertained.

Adult↗
PubMed1998

Mapping of a new target region of allelic loss to a 2-cM interval at 22q13.1 in primary breast cancer.

Allelic losses on chromosome arm 22q are frequently observed in human meningiomas and in carcinomas of the colon, ovary, and breast. Among 140 primary breast cancers we examined for loss of heterozygosity (LOH) at 16 polymorphic loci on the long arm of chromosome 22, 56 (40%) showed LOH for at least one locus. Eleven of these tumors had retained heterozygosity for markers proximal to the NF2 locus but showed LOH for markers distal to NF2. Deletion mapping indicated a new common region of deletion, 2-cM in extent, at q13.1 between Interleukin 2 receptor beta (IL2RB) and D22S279. Our results raise the possibility that one or more tumor suppressor genes associated with breast cancer may exist at 22q13.1. Comparison of these results with clinicohistological data indicated that allelic losses on 22q tend to occur more frequently in tumors of malignant histological types.

Alleles↗
PubMed1998

Mapping of a new target region of allelic loss to a 6-cM interval at 21q21 in primary breast cancers.

A detailed analysis of loss of heterozygosity (LOH) in breast cancers was performed with 11 microsatellite markers on the long arm of chromosome 21. Among the 142 tumors examined, 44 (31%) showed LOH at one or more loci. Peak LOH frequency was observed on band 21q21. Deletion mapping identified a new commonly deleted region in a 6-cM interval of 21q21 between loci D21S1432 and D21S1437, and raised the possibility that one or more tumor suppressor genes associated with breast cancer may exist in this region. Comparison of these alterations with clinicopathological parameters revealed an association of LOH on 21q with loss of progesterone receptor (P = 0.0013).

Breast Neoplasms↗
PubMed1997

Correlation of Allelic Losses and Clinicopathological Factors in Primary Breast Cancers.

Human breast cancers frequently show allelic loss or loss of heterozygosity (LOH) at apecific chromosomal regions. To understand the possible role of these genetic alterations in tumor development and progression, we examined LOH at loci on chromosomal arms 1p, 3p. 11p, 13q, 16q, 18q, and 22q in 140 to 246 cases of primary breast cancers and compared it with lymph node metastasis, histological type, tumor stage, estrogen receptor (ER) and progesterone receptor (PgR) status. LOH at 1p22-31 correlated with lymph node metastasis and a tumor size of greater than 2 cm. LOH at 13q12-14 and 18q21 were most frequently observed in tumors of the solid-tubular type. LOH at 1p34-36 was more frequent in tumors of the scirrhous and solid-tubular types than in other less aggressive histological types. Furthermore, a significant association was observed between LOH at 3p14-21, 11p11-15 and 13q12-14 and the absence of progesterone receptors. These results suggest that some clinical characteristics of breast cancers are determined by loss of tumor supperssor genes present at specific chromosomal regions.

Journal Article↗
PubMed1997

Allelic losses on 18q21 are associated with progression and metastasis in human prostate cancer.

We analyzed normal/tumor DNA pairs obtained from 46 patients with prostate cancers (stage B, 16 cases; C, 10 cases; D1, 4 cases; and endocrine therapy-resistant cancer-death, 16 cases) for loss of heterozygosity using 32 microsatellite markers on chromosome 18. Seventeen of the 46 cases (37%) showed loss of heterozygosity (LOH) for at least one locus on the long arm. Detailed deletion mapping in these tumors identified a distinct commonly deleted region within a 5-cM interval in 18q21.1. There was a statistical correlation between the frequency of LOH on 18q and clinical stage (chi 2 = 12.3; P = 0.0064). LOH on 18q was observed more frequently in Stage D1 cases (4/4; 100%) than in stage B+C cases (5/26; 19%; P = 0.0046, Fisher's exact test). In 8 of 9 (89%) cancer-death patients from whom DNAs were available from both primary and metastatic tumors, the primary tumors had either no detectable abnormality of chromosome 18 or the region involving loss of heterozygosity was limited while the metastatic foci showed more frequent and extended allelic losses on this chromosome. No abnormalities were detected in the DCC and DPC4 genes when their exons were analyzed separately by single strand conformation polymorphism assay. These results suggest that inactivation of one or more putative tumor suppressor genes on 18q21 other than DCC and DPC4 plays an important role in the progression of human prostate cancer.

Adenocarcinoma↗
PubMed1997

Localization of a breast cancer tumour-suppressor gene to a 3-cM interval within chromosomal region 16q22.

Allelic losses on chromosome 16q in tumour cells are frequent in a variety of malignancies, suggesting the presence of one or more tumour-suppressor genes in the region. Among 210 sporadic breast cancers we examined using 15 microsatellite markers on the long arm of chromosome 16, heterozygosity for at least one locus was lost in 141 (67%). Detailed deletion mapping revealed two distinct commonly deleted regions. One region was defined as a 3-cM interval flanked by markers D16S512 and D16S515 at 16q22; the second consisted of a 9.5-cM interval flanked by markers D16S498 and D16S303 at q24.3. Allelic loss on 16q was observed frequently in small tumours, tumours without lymph node metastasis and tumours of the non-invasive histological type as well as in tumours of more advanced phenotype, suggesting that inactivation of one of at least two tumour-suppressor genes on 16q plays a role in early stage breast carcinogenesis.

Breast Neoplasms↗
PubMed1997

Mapping of a breast cancer tumor suppressor gene locus to a 4-cM interval on chromosome 18q21.

DPC4 and DCC, putative tumor suppressor genes implicated in the genesis of several types of human cancer, lie on the long arm of human chromosome 18. We examined 200 primary breast cancers for allelic losses on chromosome 18, using 15 microsatellite markers distributed along the long arm. Allelic loss was detected most frequently (29-30%) at loci mapped to 18q21. Deletion mapping of the 34 tumors showing partial or interstitial deletions identified a commonly deleted region within the 4-cM interval flanked by D18S474 and D18S487 at 18q21.1-q21.3. Although this interval included the DPC4 and DCC genes, we excluded DPC4 from candidacy when polymerase chain reaction-single-strand conformation polymorphism analysis of each exon failed to detect abnormalities in any of the 54 breast cancers that exhibited loss of heterozygosity involving 18q. Allelic loss on 18q was found more frequently in tumors of the solid tubular histological type (24 of 55, 44%) than in other types (24 of 113, 21%) (P = 0.0049). The results suggest that a tumor suppressor gene located within the 4-cM region at 18q21, either DCC or another gene not yet identified, may play a role in the development of some sporadic breast cancers, particularly those of the solid tubular type.

Alleles↗
PubMed1997

PRLTS gene alterations in human prostate cancer.

Since loss of heterozygosity on 8p22-p21.3 has been found frequently in prostate cancer, the status of a candidate tumor suppressor gene named PRLTS gene, recently cloned from the same region in some human malignancies, was examined in the present study. DNAs were isolated from 69 Japanese prostate cancer patients (37 localized and 32 cancer-death cases). Loss of heterozygosity at this gene locus was observed in 15 of 36 (42%) localized prostate cancer patients and 22 of 32 (69%) cancer-death patients. One cancer-death patient had a missense mutation, ACG-->ATG (Thr-->Met) at codon 64 in metastatic tumor tissues of pelvic lymph node and liver, and these tissues showed loss of the homologous allele, indicating that "two-hit" mutation of the PRLTS gene had occurred in this case. The others did not show any mutation, regardless of the presence or absence of loss of heterozygosity. Although loss of heterozygosity at the PRLTS gene locus is a relatively common abnormality, mutation of this gene is rare in prostate cancer.

Adenocarcinoma↗
PubMed1997

Novel elements located at -504 to -399 bp of the promoter region regulated the expression of the human macrophage scavenger receptor gene in murine macrophages.

The expressions of type I and type II macrophage scavenger receptors (MSRs) are highly specific in macrophages and related cell types. Although some reports have described the regulation of MSR gene expression and proposed some cis-elements related to cell-specific expression, the regulation of MSR remains largely unclear. This is due, in part, to an unacceptably low efficiency of transfection into monocyte/ macrophage cells. In the present study, we optimized the conditions of electroporation in murine macrophage (P388D1) cells. The efficiency of electroporation was increased 20-fold compared with previous methods. Using the optimized method, we focused on studying the regulation of the human MSR promoter in macrophages. We presently demonstrate that: a) the proximal -10 to +50 bp human MSR promoter region is necessary for the cell type-specific expression of human MSR; b) the 6.5 kbp upstream sequence suppresses the expression of human MSR; c) a promoter region extending from -504 to -399 bp produced the greatest increase in transcriptional activity; d) macrophage cell-specific transcription factors bind to the region as determined by electrophoretic mobility shift assay (EMSA) and a footprint assay; and e) mutations of the region reduced about 40-75% of the promoter activity in a transfecting assay. We concluded that novel elements located at the -504 to -399 bp region may play an important role in the regulation of the MSR gene expression in macrophages. We speculate that macrophage-specific factors binding to those elements may be responsible for the transcription regulation of the MSR gene in macrophages.

Animals↗
PubMed1997

[Breast cancers].

Explore the source record for details and available documents.

Breast Neoplasms↗
PubMed1997

Detailed deletion mapping of chromosome arm 3p in breast cancers: a 2-cM region on 3p14.3-21.1 and a 5-cM region on 3p24.3-25.1 commonly deleted in tumors.

Loss of heterozygosity (LOH) on 3p is frequent in human renal cell carcinomas, lung cancers, and breast cancers. To define the region(s) on 3p that harbor presumptive tumor suppressor gene(s) for breast cancer, we examined 196 primary breast tumors for their patterns of LOH at 22 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 101 (52%) of these tumors. Detailed deletion mapping identified two distinct commonly deleted regions; one was localized to a 2-cM interval flanked by D3S1547 and D3S1295 at 3p14.3-21.1, and the other to a 5-cM interval flanked by D3S1286 and D3S1585 at 3p24.3-25.1. The FHIT gene lies in the vicinity of the proximal commonly deleted region. Attempts to correlate LOH on 3p to clinicopathological parameters detected an association with the absence of the progesterone receptor (P = 0.0096). The results suggest that inactivation of unidentified tumor suppressor genes on 3p plays a role in the mechanism whereby hormone dependency is lost in the course of breast carcinogenesis.

Breast Neoplasms↗
PubMed1996

Two distinct commonly deleted regions on chromosome 13q suggest involvement of BRCA2 and retinoblastoma genes in sporadic breast carcinomas.

BACKGROUND: Frequent allelic losses on the long arm of chromosome 13 in sporadic breast carcinomas suggest that a tumor suppressor gene(s) on 13q is involved in this type of carcinoma. The presence of a familial breast carcinoma susceptibility gene, BRCA2, and the retinoblastoma susceptibility gene (RB) on the same chromosomal arm implies that one or the other, or both, of these genes may be critically affected by those allelic losses. METHODS: To investigate the possible involvement of BRCA2 and RB in sporadic breast carcinomas, the authors examined allelic losses in 246 breast carcinomas with 14 polymorphic microsatellite markers on 13q12.q14. RESULTS: Allelic loss was observed in 95 of the 246 sporadic breast carcinomas (39%). Detailed deletion mapping identified two commonly deleted regions. The more proximal of these two segments was located in a 6-cM interval flanked by marker loci D13S289 and D13S267 and containing the BRCA2 gene; the more distal region was located in a 9-cM interval flanked by marker loci D13S328 and D13S172 and containing the RB gene. Allelic loss on 13q was found more frequently in tumors of the solid tubular histologic type (36 of 66; 55%) than in other types (52 of 146; 36%) (P = 0.0096). Furthermore, a significant association was observed between allelic loss on 13q and the absence of progesterone receptor (P = 0.0001). CONCLUSIONS: The results indicate that BRCA2 and RB are independent targets of allelic loss and that inactivation of either of these genes may play a role in the development of some sporadic breast carcinomas, particularly those of the solid tubular type.

Chromosome Mapping↗
PubMed1996

Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity.

We have molecularly cloned a cDNA for a novel protein termed Tob (Transducer of ErbB-2) that interacts with the c-erbB-2 gene product p185erbB2. Nucleotide sequencing reveals that the Tob protein is a 45 kDa protein that does not contain either SH2 (Src Homology 2) or SH3 domain but is homologous to the previously characterized anti-proliferative gene product BTG-1 at its amino-terminal half. The carboxyl-terminal half of Tob is characterized by the presence of a sequence rich in proline and glutamine and shows no homology to known proteins. Like BTG-1, exogenously expressed Tob is able to suppress growth of NIH3T3 cells, but the growth suppression is hampered by the presence of kinase-active p185erbB2. By using the GST-Tob protein that contains either full length or amino-terminal half of Tob, we show that the carboxyl-terminal half of Tob is relevant to its interaction with p185erbB2. Furthermore, we could co-immunoprecipitate the Tob protein with anti-ErbB-2 antibody, and reciprocally the p185erbB2 with anti-Tob antibodies. These data suggest that p185erbB2 negatively regulates the Tob-mediated anti-proliferative pathway through its interaction with Tob, resulting possibly in growth stimulation by p185erbB2. Finally, expression of the Tob mRNA is observed in various cell types and is not correlated with expression of c-erbB-2, suggesting that other receptor-type protein-tyrosine kinases are also involved in the Tob-mediated regulation of cell growth.

3T3 Cells↗
PubMed1996

Mutations in the BRCA1 gene in Japanese breast cancer patients.

Predisposing germline mutations in the BRCA1 gene were identified recently in families with 17 q-linked breast and ovarian cancers. Using single-strand conformation polymorphism (SSCP) analysis, we examined primary breast cancers for mutations in coding exons of BRCA1 in a panel of 103 patients, of whom all either represented early-onset cases (< 35 of age), were members of multiply-affected families, and/or had developed bilateral breast cancers. Mutations were detected in tumors from four patients, all of whom had developed breast cancers bilaterally: a frame-shift due to a 2-bp deletion at codon 797; a nonsense mutation at codon 1214; and two missense mutations, one at codon 271 leading to Val-->Met substitution, and the other at codon 1150 leading to Pro-->Ser substitution. In each case the same mutation was present in constitutional DNA. The mean age of onset was 49 years among the Japanese carriers of BRCA1 mutations identified in this study, in contrast to the mean age of 35 observed among carriers of BRCA1 mutations in a similar U.S. study (Futreal et al., 1994). The evidence reported here supports a rather limited role of BRCA1 in breast carcinogenesis.

Adult↗
PubMed1996

Three distinct commonly deleted regions of chromosome arm 16q in human primary and metastatic prostate cancers.

Human prostate cancers frequently show loss of heterozygosity (LOH) at loci on the long arm of chromosome 16 (16q). In this study, we analyzed prostate cancer specimens from 48 patients (Stage B, 20 cases; Stage C, 10 cases; cancer death, 18 cases) for allelic loss on 16q, using either restriction fragment length polymorphism (RFLP)- or polymerase chain reaction (PCR)-based methods. Allelic losses were observed in 20 (42%) of 48 cases, all of which were informative with at least one locus. Detailed deletion mapping identified three distinct commonly deleted regions on this chromosome arm: q22.1-q22.3, q23.2-q24.1, and q24.3-qter. On the basis of a published sex-averaged framework map, the estimated sizes of the commonly deleted regions were 4.7 (16q22.1-q22.3), 17.2 (16q23.2-q24.1) and 8.4 cM (16q24.3-qter). Allelic losses on 16q were observed more frequently in the cancer-death cases (11 of 18; 61%) than in early-stage tumor cases (9 of 30; 30%; P < 0.05). In 7 of 11 patients from whom DNA was available from metastatic cancers as well as from normal tissues and primary tumors, the primary cancer foci had no detectable abnormality of 16q, but the metastatic tumors showed LOH. These results suggest that inactivation of tumor suppressor genes on 16q plays an important role in the progression of prostate cancer. We also analyzed exons 5-8 of the E-cadherin gene, located at 16q22.1, in tumor DNA by means of PCR-single strand conformation polymorphism and direct sequencing, but we detected no somatic mutations in this candidate gene.

Adenocarcinoma↗
PubMed1996

Allelic losses at loci on chromosome 10 are associated with metastasis and progression of human prostate cancer.

DNA samples from tumors and paired normal tissues from 48 patients with prostate cancer (stage B, 16 cases; stage C, 14 cases; stage D, 18 cases) were examined with 26 polymorphic markers spanning chromosome 10. Allelic losses were observed in 17 of the 46 cases (37%) that were informative with at least one of the markers. Detailed deletion mapping identified two distict commonly deleted regions on the long arm of chromosome 10 (10q22-q24:7 cM and 10q25.1:17 cM) and one on 10p, suggesting that at least three tumor suppressor genes associated with prostate cancer are present on this chromosome. We observed loss of heterozygosity more frequently in tumors from fatal cases (stage D, 8/16, 50%) than in localized tumors (stage B, 0/16, 0%; P = 0.001 or stage B + C, 5/30, 17%; P = 0.02 Fisher's exact test). All metastatic tissues showed allelic loss at one or more loci on 10q. In five of the nine patients from whom DNAs were available from both metastatic and primary tumors, the primary cancer foci had no detectable abnormality of chromosome 10, while the metastatic foci showed allelic loss on chromosome 10. These results suggested that inactivation of one or more tumor suppressor genes on chromosome 10 plays an important role in late stages of prostate cancer.

Adenocarcinoma↗