ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Many types of sarcomas are characterized by specific chromosomal translocations which are likely to be of etiologic significance. The recent elucidation of the molecular structure of the several of these translocations has revealed some striking similarities. Nearly all appear to result in the production of novel, tumor-specific chimeric transcription factors. Furthermore, six of the translocations, namely the t(11;22), t(21;22), and t(7;22) of Ewing's sarcoma, the t(12:22) of clear cell sarcoma, the t(12; 16) of myxoid liposarcoma, and the t(11:22) of desmoplastic small round cell tumor, achieve this following a peculiar pattern, consisting in the fusion of a gene with an RNA-binding domain (EWSorTLS) with a transcription factor gene (FLII, ERG, ETV1, ATF-1, CHOP, orWT1). The observation that the different translocation partners of theEWSgene are specifically associated with several distinct types of primitive sarcomas suggests a model in which the translocation partner supplying the DNA-binding domain confers the target specificity of the transcriptional activation mediated by these chimeric proteins, whereas the partner supplying the N-terminal domain and promoter region determines their transactivation potential and expression level. Further analysis of the normal functions and expression patterns of these genes should yield insights into the histogenesis of these different tumor types and into normal tissue development and differentiation. Clinically, our new understanding of the molecular structure of these translocations opens new avenues for molecular diagnosis and investigative therapeutics.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Childhood cutaneous and subcutaneous malignancies are rare and include metastatic tumors of diverse histogenesis as well as primary lesions, such as sweat gland carcinomas. Some cutaneous malignancies exhibit a small round cell tumor morphology with few definitive differentiating features; they can thus pose a significant diagnostic problem. We describe two primary malignancies of the skin and superficial subcutis, which were originally diagnosed as sweat gland carcinomas on the basis of their morphological features. A cytogenetic analysis performed on one of these lesions showed the t(11;22)(q24;q12) rearrangement, believed to be unique to the Ewing's sarcoma/ peripheral primitive neuroectodermal tumor (ES/pPNET) group of neoplasms. In view of this unexpected result, reverse transcriptase-polymerase chain reaction analysis was performed on both lesions and showed that they expressedEWS/FLI-1fusion gene mRNA transcripts, the molecular equivalent of t(11;22)(q24;ql2). The two tumors also had an immunohistochemical profile suggesting ES/pPNET, including strong expression of the MIC2 antigen. Both patients were treated with wide local excision, and one was given a course of chemotherapy. Neither patient showed evidence of tumor elsewhere after follow-up periods of 2 years and 16 years. These findings suggest that these tumors are indeed a form of primary ES/pPNET arising in the skin or superficial subcutis, which may be of low-grade malignancy and curable by local surgery.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Polymerase chain reaction (PCR) amplification has been used to determine the clonal composition of tissues based on analysis of the pattern of X-chromosome inactivation, but its use has been limited by technical difficulties. This report presents an expedited method to use PCR in the analysis of clonality. The method uses gel electrophoresis of heteroduplexes formed with an artificial heteroduplex generator (HG) and PCR products from the phosphoglycerate kinase-1 (PGK-1) gene from the tissue sections. Amplification was successful in 36 of 37 cases originally diagnosed as endometrial adenocarcinoma. HG analysis of 36 cases confirmed heterozygosity in 12 cases (33.3%). PGK-1 PCR amplification product was obtained from both control and lesional tissue in 10 of the 12 heterozygous cases. Of these 10 cases, seven were shown to consist of clonal cell populations by HG analysis. Two of three cases diagnosed as well-differentiated endometrioid adenocarcinoma were found to be comprised of poly-clonal populations of cells. One case produced an anomalous pattern with HG analysis and was shown to be aneuploid by fluorescence in situ hybridization (FISH) with a chromosome X alpha-satellite probe. It is concluded that HG is a useful alternative to restriction fragment length polymorphism (RFLP) analysis of X-chromosome inactivation as a marker of tissue clonality in cases in women.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

More than half of all patients with familial or recurring venous thrombosis have hereditary resistance to activated protein C (HRAPC) as the result of a specific missense mutation in the gene for coagulation factor V Because the mutant factor Va (with an Arg to Gin substitution at codon 506) cannot be cleaved and inactivated by activated protein C. carriers of this mutation are at significantly increased risk of venous thrombosis. We have recently introduced a direct polymerase chain reaction (PCR)-based clinical diagnostic test for the factor V codon 506 mutation based on the destruction of anMnlI restriction site by the causative nucleotide substitution. To assess the accuracy of this PCR-based assay, we compared a functional clotting time test for HRAPC with the direct mutation test. Of 47 patients dually tested, only five had discrepant values for the functional test versus the DNA test. Either of these two complementary assays is useful for the accurate diagnosis of HRAPC. The DNA-based test is, however, specifically recommended for evaluation of anticoagulated patients or patients with borderline functional tests and confirmation of genotype in HRAPC families. In an additional analysis of 287 normal individuals, we found an extremely high prevalence of the mutated codon 506 allele—∼4% in each of two different populations. The absence of disease in the majority of heterozygous carriers suggests that symptomatic thrombosis requires the simultaneous presence of both a mutated factor V protein and additional synergistic factors.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

One hundred and fifty colorectal adenomas were investigated in order to detect the presence of K-rasgene mutation. The adenomas were classified according to the severity of the histological lesion (mild, moderate, or severe dysplasia and carcinomatous transformation) and to the degree of aneuploidy. K-rasmutation was found in 30.8% of cases, mostly consisting of a point mutation of codon 12. K-rasmutation was more frequently found in adenomas >1 cm and in the villous type. No correlation was otherwise demonstrable with the ploidy pattern of the lesion.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Reviewing studies of alterations of theTP53tumor suppressor gene in human breast carcinomas gives cautious optimism aboutTP53alterations as a prognostic marker in this disease. For the time being, breast carcinomas should be screened forTP53alterations at both the protein and gene levels. Improved mutational screening techniques are needed for this purpose. We consider constant denaturant gel electrophoresis, a modification of denaturing gradient gel electrophoresis, to represent such an improvement. With the recent development of the BioRadD GENEsystem, constant denaturant gel electrophoresis screening forTP53mutations can easily be performed on large series of breast carcinomas.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Acute leukemias containing >3% myeloperoxidase (MPO)-positive blast cells, as detected cytochemically, are considered to be myelogenous in origin, regardless of the immunophenotypic markers expressed. Conversely, acute leukemias that express only myeloid antigens are also considered to be acute myelogenous leukemia (AMD, even in the absence of MPO. These MPO-negative AMLs, designated AML-M0 in the FAB classification, currently require either immunophenotypic or electron microscopic studies for identification. To examine the association of MPO and myeloid antigen expression in AML, particularly at the early stages of myeloid cell differentiation, we have used in situ hybridization (ISH) to evaluate MPO gene expression in myeloid leukemia cell lines and a variety of well-characterized acute leukemias, including six cases of AML-MO. Strong positivity for MPO mRNA was detected in the myeloid leukemia cell line HL-60 and in 22 of 27 AMLs (three AML-MO, four AML-M1, eight AML-M2, five AML-M4, two AML-M5a). No MPO gene expression was detected in three AML-MO, one AML-M5a, one AML-M7, 5 acute lymphoblastic leukemia, the lymphoid cell lines Molt-4 and Namalwa, or in the early myeloid cell lines KG-1 and KG-la. Ultrastructural studies for MPO activity were performed on four AML-M0; one leukemia showed both gene expression and cytochemical activity, whereas two others contained neither MPO transcripts nor enzyme. Weak MPO gene expression was evident in one AML-M0 that was negative for enzymatic activity by electron microscopy. These studies show that MPO gene expression can be detected by ISH in about half of AML-M0, supporting their presumed myelocytic derivation. However, the blasts in some AML-M0 fail to express MPO, even at the molecular level, suggesting that these cells are at a very early stage of myeloid commitment or that differentiation along some other nonlymphoid cell line may be present.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Estrogen receptors (ER) are detected in 50–85% of all breast tumors, and are clinically important because they tend to identify patients with a higher probability of responding to hormonal or endocrine manipulations. However, ∼30–40% of all ER+patients do not respond to hormonal manipulations. The lack of response to hormonal manipulations in ER+patients could be the result of nonfunctional ER, as determined by its inability to recognize and bind to specific DNA-responsive elements and/or its inability to recruit other transcriptional activation factors. The functional status of ER in 34 human breast tumors was assessed by determining the structural integrity of the ER DNA-binding domain using site-directed monoclonal anti-estrogen receptor antibody and sucrose density gradient analysis. Based on the fraction of ER containing an intact DNA-binding domain, the tumors were classified into three groups: group I with >65% of intact ER, group II with >30% of intact ER. and group III with <30% of intact ER. Clinical and pathologic data were obtained only for patients who were treated with the anti-estrogen tamoxifen and correlated with ER functional status. In group I, 11 of 13 (84.6%) patients were responsive to hormonal therapy with favorable clinical outcome; two patients had unfavorable clinical outcome. In group II, 13 of 15 patients (86.7%) had favorable clinical outcome and two patients (13.3%) had unfavorable outcome. In group III, three of six patients appeared to be hormone responsive with favorable clinical outcome, and three of the patients in this group had unfavorable response to therapy. ER functional status may be linked to hormone responsiveness in breast cancer and the resistance of some ER+tumors to anti-estrogen treatment may be explained, in part, by dysfunctional ER. This approach may permit the development of new clinical assays based on ER functional status, which could facilitate selection of patients who are likely to benefit from anti-estrogen therapy.

ISSN:1052-9551    

出版商:OVID    

年代:1995

数据来源: OVID