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Biomedical subjects

M Miyaki

Publications and source records attributed to M Miyaki.

At least 37 records · Page 2Linked to original sources
PubMed1999

Suspected hereditary nonpolyposis colorectal cancer: International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) criteria and results of genetic diagnosis.

PURPOSE: The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary nonpolyposis colorectal cancer. METHODS: We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I and II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp, at least one colorectal cancer case diagnosed before the age of 50, and occurrence of a hereditary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, or ovary) in family members. Criteria II consist of one colorectal cancer patient with at least one of the following: early age of onset (<40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling (one aged <50 years); and two siblings with other integral hereditary nonpolyposis colorectal cancer extracolonic cancers (one aged <50 years). A questionnaire was mailed to members of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria. For comparison the mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria in each institution was also obtained. RESULTS: Data were obtained from eight different institutions (in 7 different countries). In a total of 123 patients from 123 families (67 families fulfilling Criteria I and 56 families fulfilling Criteria II), genetic testing for germline mismatch repair gene variants was performed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families fulfilling Criteria I was 28 percent (19/67). The mutation detection rate for families fulfilling Criteria II was 9 percent (5/56). In these eight institutions, the overall mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154). CONCLUSION: The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and they can include extracolonic cancers. The results of this study suggest that families fulfilling Criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling Criteria II suggests that, using current techniques, genetic testing in these families is not practical.

Age of Onset↗
PubMed1999

Rectal cancer in a 13-year-old boy without a detectable germline mutation in FAP and HNPCC genes.

Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by familial clustering and early onset. It is unclear, however, whether the early onset of colorectal cancer necessarily represents HNPCC. A 13-year-old patient had rectal cancer and underwent curative surgery. DNA from this patient was examined for replication errors (RER) and genes related to familial colorectal cancer (APC, hMSH2, and hMLH1). The patient had a negative family history of colorectal cancer, did not show the RER phenotype, and had no germline mutation of the APC, hMSH2, and hMLH1 genes. The present case suggests that an unusually young patient with colorectal cancer is not always an HNPCC proband. Observation over time, however, will be needed, as a first mutator of familial colorectal cancer could be missed.

Adenocarcinoma, Mucinous↗
PubMed1999

Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis.

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 210-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.

Adenomatous Polyposis Coli↗
PubMed1999

A novel case of a sporadic desmoid tumour with mutation of the beta catenin gene.

A 42 year old man without familial adenomatous polyposis had recurrent desmoid tumours in the left subclavicular site. Histological examination showed a typical desmoid tumour. Molecular analysis was performed in genomic DNA from this tumour, using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing methods. No mutation could be detected in the entire coding sequence of the APC gene, nor in H-ras, K-ras, N-ras, or p53 genes. On seeking a mutation of the beta catenin gene (CTNNB1), an activating mutation from ACC (Thr) to GCC (Ala) at codon 41 was found. Immunohistochemical staining showed that accumulated beta catenin protein was predominantly localised in the nuclei of desmoid cells. This is the first example of a sporadic desmoid tumour in which a mutation of the beta catenin gene was revealed.

Adult↗
PubMed1998

Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue.

BACKGROUND: The authors examined somatic mutations of the adenomatous polyposis coli (APC) gene in 84 human aberrant crypt foci (ACF) to determine whether APC gene mutations were involved in the histologic progression of ACF. METHODS: Mutation cluster regions of the APC gene were subjected to polymerase chain reaction single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Four kinds of deletion were detected in the mutation cluster regions of APC gene in five ACF. APC mutation was detected in 1 of 18 ACF with Stage I abnormalities (6%). Four of 10 adenomatous ACF (40%) harbored the mutation. There were no mutations in 56 hyperplastic ACF. CONCLUSIONS: These results suggest that APC mutations may be involved initially in only a limited number of adenomas in ACF.

Adenomatous Polyposis Coli↗
PubMed1998

Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors.

BACKGROUND: DNA replication errors (RERs) are closely associated with hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently, alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and hPMS2, have been implicated in the pathogenesis of HNPCC: Several studies have demonstrated RER in 13-17% of nonfamilial colorectal carcinomas. It is unclear, however, as to whether or not these RER positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC or are caused by incidental alterations of DNA mismatch repair genes. Consequently, the authors studied the characteristics of RER positive nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2 and hMLH1 gene mutations. METHODS: Fresh or frozen samples of 103 nonfamilial colorectal carcinomas were examined for RERs using the polymerase chain reaction (PCR) and specific microsatellite primers. The authors also identified mutations of the hMSH2 and hMLH1 genes in RER positive samples by a PCR single strand conformational polymorphism analysis followed by direct nucleotide sequencing. RESULTS: The incidence of RER was 15.7% (17/103) in nonfamilial colorectal carcinomas, and only 1 case, which was found in the ascending colon, showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any of the remaining RER positive tumors. RER positive nonfamilial carcinomas tended to be located more frequently in the right colon. There was no increased prevalence in young patients, and the clinicopathologic characteristics of HNPCC were absent in the patients with RER positive nonfamilial colorectal carcinoma. CONCLUSIONS: Based on these findings, the carcinogenesis of RER positive nonfamilial colorectal carcinoma is considered different from that of HNPCC:

Adaptor Proteins, Signal Transducing↗
PubMed1997

Drastic genetic instability of tumors and normal tissues in Turcot syndrome.

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.

Adenocarcinoma↗
PubMed1997

Expression of CD44 variants in gastric carcinoma with or without Epstein-Barr virus.

The significance of CD44 variants in gastric carcinoma has not been fully investigated in terms of the pathological features of the carcinoma, including its association with Epstein-Barr virus (EBV). In this study, a total of 104 primary gastric carcinoma tissues (EBV-associated gastric carcinomas, EBVaGC, and EBV-negative carcinomas) were evaluated by immunohistochemistry. When the immunoreactivity of formalin-fixed, paraffin-embedded sections was graded on a scale of 0-3, the frequencies of grades 0-1, 2 and 3 were, respectively, 77%, 16% and 7% using monoclonal antibody (MAb) 3G5, which recognizes V3-5, and 70%, 14% and 15% with MAb 2F10, which recognizes V6. The expression of CD44 variants is independently correlated with lymph node metastasis and EBV-association in gastric carcinoma. Significant correlations were observed between V3-5 expression and lymph vessel invasion or lymph node metastasis, and between V6 expression and lymph node metastasis. The expression of both variants was significantly correlated with EBV-association. EBV-association and lymph node metastasis contributed independently to CD44 variant expression by multivariate analysis. Thus, the mechanism and significance of CD44 variant-expression are different in gastric carcinomas with or without EBV. EBVaGC is a distinct type of gastric carcinoma which should be considered separately from EBV-negative carcinoma.

Adolescent↗
PubMed1997

Cell activation by the micropatterned surface with settling particles.

Surface topography plays an important role in cell orientation and morphogenesis. In this study, we prepared a micropatterned surface with settling particles to obtain more detailed information about the cell recognition against the microstructured surface. Core-shell type particles having a poly-(N-isopropylacrylamide) (polyNIPAM) shell were prepared by seeded polymerization. Particles were settled on a polystyrene (PSt) flat dish by the spinner to prepare a micropatterned surface with settling particles. It could be seen that the polyNIPAM shell shrunk above and swelled below the LCST. For comparison, a thermosensitive flat surface was prepared by the graft polymerization of NIPAM. No morphologic change of cells contacting the both surfaces was observed with either an optical or a scanning electron microscope. Moreover, particles could move or roll on these surfaces when shaking the dishes. The weak interaction between neutrophil-like cells and the micropatterned surface with settling particles or the polyNIPAM-grafted surface was estimated by measurement of active oxygen released by cells. A little release could be observed at both 25 and 35 degrees C. The amount of released active oxygen at 35 degrees C was slightly larger than at 25 degrees C. When the temperature was suddenly changed, the dynamic changes of particle shape and size resulted in the excess release of active oxygen from cells contacting the micropatterned surface with settling particles. Meanwhile no stimulation could be observed in the polyNIPAM-grafted surface even if the temperature is suddenly changed. These results indicate that the micropatterned surface with settling particles can induce the dynamic stimulus at a patterned input mode.

Acrylic Resins↗
PubMed1997

Microsatellite instability and loss of heterozygosity in gastric lymphoma.

To evaluate the significance of microsatellite instability (MI) and loss of heterozygosity (LOH) in the development of gastric lymphoma, we examined 33 tissue-samples of 20 primary gastric B-cell lymphomas (6 low-grade lymphomas of mucosa-associated lymphoid tissue [MALT; 10 samples] and 14 diffuse large B-cell lymphomas [23 samples]). MI and LOH were evaluated at 13 microsatellite loci. In MALT lymphoma, four of six cases showed MI at one to two microsatellite loci (average 1.0 per case, 0.8 per sample), whereas in diffuse B-cell lymphoma, all samples showed MI at one to five microsatellite loci (average 2.4 per case, 2.7 per sample) (p < 0.05 and p = 0.0001). MI at the c-myc gene locus was most frequent in both types of gastric lymphomas (3 of 6 and 11 of 14 cases, respectively). Regional heterogeneity of the MI pattern was observed in two of four cases of MALT lymphoma and in four of five cases of diffuse B-cell lymphoma. On the other hand, LOH was observed only in one MALT lymphoma and in three diffuse B-cell lymphomas. Genetic instability may be an important mechanism for the development and progression of gastric lymphoma. Frequent MI at the c-myc locus might reflect an activated state and the importance of this gene in mucosal lymphocytes of chronic gastritis.

Adult↗
PubMed1996

p300 gene alterations in colorectal and gastric carcinomas.

Colorectal tumors frequently have loss of heterozygosity on chromosome 22q, suggesting that inactivation of tumor suppressor gene(s) on 22q participates in the tumor development. Neurofibromatosis 2 (NF2) gene and E1A binding protein p300 gene, recently identified on 22q, are thought to be candidates for tumor suppressor genes. In this study, mutation of the NF2 gene in 59 colorectal carcinomas, and mutation of the p300 gene in 27 colorectal and two gastric carcinomas, were analysed using PCR-SSCP, RT-PCR-SSCP and direct sequencing methods. Missense mutations of p300 gene were detected in a colorectal carcinoma, and in a gastric carcinoma, though no mutation of NF2 gene was detected. Both p300 mutations were somatic and coupled to deletion of the second allele of the gene, which suggests inactivation of the p300 gene, in these carcinomas. The mutations are located within the Cys/His-rich regions, which are assumed to play important roles in the function of p300. These are the first cases in which p300 gene has been found to be altered in both alleles, suggesting that inactivation of the p300 gene may be involved in the development of carcinomas, and that this gene may be the target of loss of 22q in carcinomas of the digestive tract.

Base Sequence↗
PubMed1996

Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma.

BACKGROUND: Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. METHODS: Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. RESULTS: Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. CONCLUSIONS: These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients.

Adenoma↗
PubMed1996

Suppression of tumorigenicity and invasiveness of colon carcinoma cells by introduction of normal chromosome 8p12-pter.

The development of human colon carcinomas is associated with a number of genetic alterations. A high frequency of deletion of the short arm of chromosome 8 at a late stage of colon carcinogenesis was detected by DNA analysis of colon carcinomas, which suggests the presence of a tumor suppressor gene. We therefore, introduced normal human chromosome 8 into colon carcinoma cells that showed allele loss on 8p21, through microcell hybridization. Five clones of hybrid cells were obtained from independent experiments. Three hybrids exhibited morphological alteration and suppressed tumorigenicity in the subcutis of nude mice, but the other two did not. The difference between the two types of hybrids was the region of the introduced normal chromosome 8: Three hybrids exhibiting morphological alteration and suppressed tumorigenicity had the entire region of the introduced chromosome 8, whereas the other two, exhibiting no change, lacked 8p12-pter from the introduced chromosome. Furthermore, the invasiveness of the hybrids with suppressed tumorigenicity was reduced to one-fifth of that of the parental cells. These results indicate that 8p12-pter carries a gene that contributes to suppression of both tumorigenicity and invasiveness of colon carcinomas.

Animals↗
PubMed1996

Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.

BACKGROUND & AIMS: Microsatellite instability (replication error [RER]) is a characteristic of tumors in hereditary nonpolyposis colon cancer (HNPCC), but the mechanism of HNPCC carcinogenesis is not yet understood. To clarify the nature of HNPCC tumors, RER and genetic changes were compared between HNPCC and non-HNPCC tumors. METHODS: RER and genetic changes were analyzed in 21 HNPCC, 389 familial adenomatous polyposis, and 206 sporadic tumors using polymerase chain reaction, single-strand conformation polymorphism, sequencing, and Southern hybridization. RESULTS. in HNPCC, 95% tumors at all stages showed RER positivity (altered loci, 4.3 of 5). In familial adenomatous polyposis and sporadic tumors, RER positivity (1.7 of 5) was 3% in adenoma and intramucosal carcinoma, 13%-24% in invasive carcinoma, and 35% in carcinoma metastasized to liver. Fifty percent of RER-positive HNPCC tumors had both germline and somatic mutations of hMSH2 or hMLH1 gene, whereas 6% of RER-positive non-HNPCC had somatic mutation. APC, p53, and K-ras-2 mutations and loss of heterozygosity of tumor-suppressor genes were significantly less frequent (P = 0.03 to 0.0006) but transforming growth factor beta type II receptor mutation was significantly more frequent (P = 0.000001) in HNPCC than in non-HNPCC. CONCLUSIONS: RER positivity occurs from an early stage of carcinogenesis in HNPCC but in later stages in non-HNPCC. Most HNPCC tumors may develop through different genetic changes from those in the adenoma-carcinoma sequence, although a certain percentage develops through APC mutation.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Increased cell-substratum adhesion, and decreased gelatinase secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells.

Metastasis of colon carcinomas is assumed to be caused by multiple steps, which include a loss of cell adhesion that results in the release of carcinoma cells from the original tumor tissue. A human colon carcinoma cell line COKFu was established from a poorly differentiated metastatic adenocarcinoma without cell-cell adhesion and without expression of E-cadherin mRNA and protein. This cell line was co-transfected with mouse E-cadherin cDNA in an expression vector and a neomycin-resistant gene. The parental carcinoma cells had a spindle shape and were scattered, whereas the transfected cells, which expressed exogenous E-cadherin gene, showed a more compact shape with strong cell-cell adhesion and with increased adhesiveness to collagen gel. These cells showed a significantly low anchorage independency (2-7%) and decreased invasiveness (30%) compared to the parental cells. Growth rate of transfectants was decreased both in vitro and in the subcutis of nude mice, with decreased lymphnode metastasis in the case of intravenous injection. It was additionally found that activity of 62 kd gelatinase, secreted from parental cells, was lost or decreased in E-cadherin-transfected cells. These results suggest that E-cadherin is not only involved in the cell-cell adhesion of colon carcinomas, it also has a wider effect, including cell-substratum adhesion and the regulation of proteinase secretion from the cells, resulting in partial suppression of invasiveness and tumorigenic growth.

Animals↗