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PubMed1996

Gene therapy for malignant neoplasms of the CNS.

Five different gene transfer protocols have progressed into human clinical trials for the treatment of brain tumors. Two utilize the in vivo transfer of the Herpes Simplex-thymidine kinase (HS-tk) gene by either retroviral or adenoviral gene transfer. HS-tk confers a sensitivity to the anti-herpes drug ganciclovir (GCV). Insertion of HS-tk into tumors and subsequent treatment with GCV has successfully eliminated tumors in experimental animal models despite less than a 100% gene transfer efficiency. This phenomenon, the 'bystander effect', allows the destruction of neighboring tumor cells not transduced with HS-tk. Two other approaches use ex vivo gene transfer of either the IL-2 or antisense insulin-like growth factor type 1 (IGF-1) genes into autologous tumor cells. In animal models, tumor cells genetically altered with antisense IGF-1 or IL-2 genes induce a potent cell-mediated antitumor response. The fifth approach uses the genetic modification of hematopoietic stem cells instead of tumor cells. In this approach, the multiple drug resistance (MDR-1) gene is transferred into stem cells to protect them from the toxic effects of certain chemotherapy drugs. This may allow the administration of higher doses without increasing bone marrow toxicity. Together, these clinical trials will provide critical information needed to develop improved gene transfer technologies for humans and to attain clinical benefit for cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1980

Site-directed chromosome rearrangements in skin fibroblasts from persons carrying genes for hereditary neoplasms.

Chromosomal variability was studied in cultured skin fibroblasts in members of two unrelated families associated with hereditary neoplasms, one with familial childhood leukemia and the other with medullary thyroid cancer syndrome. Nonconstitutional chromosome rearrangements occurred with consistent frequency in the patients and obligate carriers. The G-banding analysis showed that th chromosome rearrangements were not random, and site of rearrangements tended to cluster to band p22 of chromosome 1 in the carriers of childhood leukemia gene and to band q23 of chromosome 17 in the patient with medullary thyroid cancer. The de novo rearrangements of chromosomes and their tendency to cluster to particular chromosomal sites strongly point to the possibility that the procancer type-dominant mutations responsible for these diseases have a mutator function analogous to the property of some insertion mutations or transposable elements.

Cells, Cultured↗
PubMed1996

Potential false-positive results with antigen enhancement for immunohistochemistry of the p53 gene product in colorectal neoplasms.

Immunohistochemistry (IHC) for intranuclear p53 gene product is a simple, routine alternative to molecular genetic analysis of the p53 gene. Several methods for antigen enhancement are currently in use for IHC. This study evaluates the effect of extreme antigen enhancement for p53, using a monoclonal antibody (DO7) and a polyclonal antibody (CM1). The cases studied were five colorectal carcinomas, two specimens of normal colorectal mucosa, and four colorectal carcinomas with genetic alterations which are expected to preclude p53 gene product expression, namely mutation to a STOP codon in the p53 gene detected by denaturing gradient gel electrophoresis with subsequent sequencing and allelic loss of 17p in the region where p53 is located, detected by restriction fragment length polymorphism analysis. The findings suggest that extreme antigen enhancement may cause false-positive results with a distinct nuclear staining pattern when MAb DO7 is used as a primary antibody. It is concluded that all antigen enhancement methods should be thoroughly tested to evaluate their validity and that there may be a limit to the extent to which antigen enhancement can be applied in IHC for p53 protein.

Antibodies, Monoclonal↗
PubMed1994

An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms.

Immunohistochemical detection of intranuclear p53 gene product may indicate mutation of the p53 suppressor gene on chromosome 17p. We used six commercially available antibodies for p53 immunohistochemistry on 19 archival colorectal neoplasms and compared the results with the mutation status of the p53 gene and 17p allelic deletion status. By Friedman's ranking analysis, use of mouse monoclonal antibody DO7 with Target Unmasking Fluid (TUF) for antigen retrieval was the most sensitive and specific procedure (P < 0.0001). Six of 7 cases with high expression (p53 Labeling Index > 30 per cent using a CAS 200 image analyser) had p53 mutation. Of seven tumours without expression (LI < 1 per cent), six had no mutation and one had a truncating mutation which prohibited nuclear localization of gene product. The low expression group (1 per cent < LI < 30 per cent, n = 5) consisted of three tumours without and two tumours with mutation. The sensitivity of high expression with the DO7-TUF method for p53 gene mutation was 67 per cent with specificity of 90 per cent, predictive value of a positive of 86 per cent, predictive value of a negative of 75 per cent, and efficiency of 79 per cent. This study suggests that immunohistochemistry is valuable for assessing p53 gene mutations in colorectal neoplasms, but further study is needed to elucidate the precise link between immunohistochemistry and molecular genetic alterations.

Antibodies↗
PubMed2001

Conjunctival T-cell lymphoma caused by human T-cell lymphotrophic virus infection.

PURPOSE: To examine the cause of adult T-cell leukemia/lymphoma. METHODS: We examined a conjunctival biopsy from a 29-year-old Jamaican man who developed bilateral conjunctival masses. Adult T-cell leukemia/lymphoma was diagnosed using routine histology, immunohistochemistry, electron microscopy, microdissection, and the polymerase chain reaction. RESULTS: Histopathologic examination revealed a conjunctival lymphoma. Clonality of the T-cell receptor gamma gene and human T-cell lymphotrophic virus gag gene were detected in the malignant cells. The demonstration of the human T-cell lymphotrophic virus gene and the rearrangement of the T-cell receptor gene in this neoplasm provide proof that human T-cell lymphotrophic virus is the cause of this conjunctival T-cell lymphoma. CONCLUSION: Human T-cell lymphotrophic virus is the cause of adult T-cell leukemia/lymphoma, an aggressive malignancy of CD4+ lymphocytes.

Adult↗
PubMed1991

Inactivation of the retinoblastoma gene in human lymphoid neoplasms.

The absence of wild type retinoblastoma (Rb) gene expression in a wide variety of human solid tumors suggests an etiologic role for this tumor suppressor gene in human cancer. We have evaluated the involvement of Rb gene inactivation in the pathogenesis and progression of human lymphoma and leukemia. We examined the genomic configuration and transcription of the Rb gene in cultured cell lines and primary cases of T- and B-cell lymphomas and leukemias. By Southern analysis, abnormalities of the Rb locus were identified in 1 of 5 T-cell acute lymphoblastic lymphoma (T-ALL) cell lines, 1 of 26 primary cases of T-ALL, 1 of 40 primary cases of chronic lymphocytic lymphoma/well-differentiated lymphoma (CLL/WDL), and 1 of 15 primary cases of intermediately differentiated lymphoma (IDL). By Northern analysis, markedly reduced or abnormal expression of the Rb gene was identified in 2 of 5 T-ALL cell lines, 1 of 7 primary cases of T-ALL, 1 of 5 primary cases of CLL/WDL, and 1 of 6 primary cases of IDL. These findings show that Rb gene inactivation can be associated with a broad range of lymphoid neoplasms and that loss of the tumor suppressor function of Rb may influence the pathogenesis and progression of lymphoma/leukemia.

DNA Probes↗
PubMed2003

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms.

The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2'-deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dose-dependent cell proliferation in a SOCS-1-methylated cell line (PL10, P=0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.

Adult↗
PubMed1989

Abnormal methylation of the calcitonin gene in human colonic neoplasms.

Earlier studies of the methylation status of total genomic DNA and of specific genes have demonstrated, predominantly, hypomethylation in human neoplasms. However, we have recently documented the presence of new sites of methylation in the calcitonin gene in human lymphomas (100%), small cell lung carcinomas (92%), and acute myeloid leukemias (95%). We now report that these same novel calcitonin gene methylation sites are also a feature of DNA from human colonic adenomas (13 out of 14 studied), colon carcinomas (4/13), and established colon carcinoma cell lines (18/19), despite the presence of overall genomic DNA hypomethylation in these neoplasms. The data provide further evidence that regional increases in DNA methylation, like gene hypomethylation, occur in benign colonic neoplasms prior to malignant transformation. The fact that abnormalities of calcitonin gene methylation are less frequent in DNA from human colonic carcinomas than from adenomas and colon carcinoma cell culture lines is of special interest. This finding suggests that a more heterogeneous population of cells is present in the carcinomas and that the calcitonin gene hypermethylation may be inherent to cells which are initially selected for growth in culture or are capable of prolonged survival under culture conditions.

Adenoma↗
PubMed1987

T cell gamma gene rearrangements in hematologic neoplasms.

Rearrangements of the T cell gamma (T gamma) gene were studied in primary neoplastic cells from 75 patients with leukemia or lymphoma. T gamma gene rearrangements were observed in 19 of 21 T cell neoplasms; 14 of 21 immature B cell leukemias, including 4 out of 5 patients with rearrangements of both immunoglobulin heavy-chain (JH) and T cell receptor beta chain (T beta) genes; none out of 16 nonlymphoid leukemias. Thus, T gamma gene rearrangement is frequently found in immature B cells and is not always found in T cells showing T beta gene rearrangement, but it is not detected in nonlymphoid cells. Furthermore, T gamma gene rearrangement in cells with the germline configuration of the JH and T beta genes was observed. These results indicate that the detection of T gamma gene rearrangement does not allow a clear assignment to a particular lineage. However, an analysis of T gamma gene rearrangement provides a further potential tool to establish the lymphoid cellular origin and clonality of hematologic neoplasms and identify the normal stages of lymphocyte differentiation.

B-Lymphocytes↗
PubMed1990

T-cell receptor gene rearrangements and the diagnosis of human T-cell neoplasms.

The rearranging antigen receptor genes of lymphoid cells serve as unique clonal markers of lymphoid neoplasms. Gene rearrangement analysis is a highly sensitive and reproducible tool which is useful in the diagnosis and classification of malignant lymphoma/leukemia. Although clonality can often be determined among B cell neoplasms by virtue of immunoglobulin isotype analysis, no such phenotypic marker of clonality exists for T cells. Therefore, clonality of T lymphoproliferative processes is most readily determined by rearrangement analysis of the T cell antigen receptor genes. The alpha, beta, gamma, and delta genes of the T cell receptor gene family encode heterodimeric surface antigen receptors and undergo rearrangement early in T cell differentiation. Identification of rearrangement of T cell antigen receptor genes provides valuable diagnostic information concerning cellular lineage, clonality and classification of T cell neoplasms. This molecular approach is applicable to the diagnosis of occult disease, relapse, and resolution of diagnostic dilemmas in any type of tissue sample including fluids and needle aspirations.

Gene Rearrangement, T-Lymphocyte↗
PubMed2005

[Expression of SSX2 gene in human urologic neoplasms].

OBJECTIVE: To investigate the expression of SSX(2)gene in human renal cell carcinoma and urinary transitional cell carcinoma. METHODS: Reverse-transcription polymerase chain reaction (RT-PCR) was used for detecting SSX(2) gene in the specimens from renal cell carcinoma (n = 26), urinary transitional cell carcinoma (n = 27) and in 15 specimens taken from the tumor surrounding tissues. RESULTS: Positive expression of SSX(2) gene at mRNA was detected in 69% renal cell carcinomas (18/26), in 81% urinary transitional cell carcinomas (22/27). The mRNA of SSX(2) was not detected in the 15 specimens from tumor surrounding tissues. CONCLUSION: The SSX(2) gene is highly expressed in human renal cell carcinoma and urinary transitional cell carcinoma.

Adult↗
PubMed1998

Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation.

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.

CpG Islands↗