公开(公告)号：EP1430071A1

公开(公告)日：2004-06-23

申请号：EP02773302.1

申请日：2002-09-09

申请人： The Johns Hopkins University School of Medicine

发明人： BUCKHAULTS, Phillip ,  KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

IPC分类号： C07H21/04

CPC分类号： C07K14/495 ,  C07K14/47 ,  C07K14/705

摘要： Serial analysis of gene expression (SAGE) was used to identify transcripts encoding secreted or cell-surface proteins that were expressed in benign and malignant tumors of the colorectum. A total of 290,394 tags were analyzed from normal, adenomatous and cancerous colonic epithelium. Of the 21,343 different transcripts observed, 957 were found to be differentially expressed between normal and adenoma or between normal and cancer. Forty-nine transcripts were elevated ≥ 20-fold in adenomas, 40 transcripts were elevated ≥ 20-fold in cancers, and nine transcripts were elevated ≥ 20-fold in both. Product of six these nine transcripts (TGFBI, LYS, RDP, MIC-1, REGA, and DEHL) were predicted to be secreted or to reside on the cell surface and these were analyzed in more detail. The abnormal expression levels predicted by SAGE were confirmed by quantitative PCR analyses of each of these six genes. Moreover, the cell types responsible for the elevated expression were identified by in situ hybridization and by PCR analyses of epithelial cells immunoaffinity purified from primary tumors.

公开(公告)号：EP1343884A2

公开(公告)日：2003-09-17

申请号：EP01270126.4

申请日：2001-12-12

申请人： The Johns Hopkins University

发明人： YU, Jian ,  KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

IPC分类号： C12N15/12 ,  C07K14/47 ,  G01N33/50 ,  C12N15/62 ,  C12N15/11

CPC分类号： G01N33/5011 ,  C07K14/4747 ,  C07K2319/00 ,  G01N2500/20

摘要： Through global profiling of genes that were expressed soon after p53 expression, we identified a gene termed (JFY1). The protein encoded by (JFY1) was found to be exclusively mitochondrial and to bind to Bcl-2 and Bcl-XL through a BH3 domain. Exogenous expression of (JFY1) resulted in an extremely rapid and profound apoptosis that occurred much earlier than that resulting from exogenous expression of p53. Based on its unique expression patterns, p53-dependence, and biochemical properties, (JFY1) is likely to be a direct mediator of p53-associated apoptosis.

公开(公告)号：EP1255856A2

公开(公告)日：2002-11-13

申请号：EP00952304.4

申请日：2000-07-31

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q1/6818 ,  C12Q1/6851 ,  C12Q1/686 ,  C12Q1/6874 ,  C12Q2600/156 ,  C12Q2600/158

摘要： The identification of pre-defined mutations expected to be present in a minor fraction of a cell population is important for a variety of basic research and clinical applications. The exponential, analog nature of the polymerase chain reaction is transformed into a linear, digital signal suitable for this purpose. Single molecules can be isolated by dilution and individually amplified; each product is then separately analyzed for the presence of mutations. The process provides a reliable and quantitative measure of the proportion of variant sequences within a DNA sample.

公开(公告)号：EP1104492A1

公开(公告)日：2001-06-06

申请号：EP99943742.9

申请日：1999-08-20

申请人： The Johns Hopkins University,School of Medicine,Office of Technology Licencing

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  POLYAK, Kornelia

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6809 ,  C12Q1/6886 ,  C12Q2600/156

摘要： The accumulation of homoplasmic somatic mutations has been observed in the mitochondrial DNA of certain tumor cells. The presence or a recurrence of a tumor can be detected by determining the presence of single basepair mutations in the mitochondrial genome from a cell sample of a patient.

公开(公告)号：EP1104475A1

公开(公告)日：2001-06-06

申请号：EP99943741.1

申请日：1999-08-20

申请人： The Johns Hopkins UNiversity School of Medicine

发明人： HE, Tong-Chuan ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/63 ,  C12Q1/68 ,  C07K14/27

CPC分类号： C07K14/47 ,  A61K38/00 ,  A61K48/00 ,  C07K14/4705 ,  C12Q1/6897

摘要： The APC tumor suppressor protein binds to β-catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium (hTcf-4) was cloned and characterized. hTcf-4 transactivates transcription only when associated with β-catenin. Nuclei of APC-/- colon carcinoma cells were found to contain a stable β-catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed β-catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating β-catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of β-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of β-catenin is critical to APC"s tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β-catenin.

公开(公告)号：EP0580596B1

公开(公告)日：2000-07-12

申请号：EP92905276.9

申请日：1992-01-16

申请人： THE JOHNS HOPKINS UNIVERSITY ,  THE UNIVERSITY OF UTAH ,  THE CANCER INSTITUTE OF JAPANESE FOUNDATION FOR CANCER RESEARCH

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  WHITE, Raymond, L. ,  NAKAMURA, Yusuke

IPC分类号： C12Q1/68 ,  C12N15/12

CPC分类号： C07K16/3046 ,  C07K14/47 ,  C12Q1/6886 ,  C12Q2600/118

摘要： A new human gene termed MCC is disclosed. Methods and kits are provided for assessing mutations of the MCC gene in human tissues and body samples. Gross rearrangement and point mutations in MCC are observed in human tumor cells. MCC is expressed in most normal tissues. These results suggest that MCC is a tumor suppressor.

公开(公告)号：EP0507852B1

公开(公告)日：1998-04-01

申请号：EP91902391.1

申请日：1990-12-19

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： VOGELSTEIN, Bert

IPC分类号： C12Q1/68 ,  C12P19/34 ,  G01N33/574 ,  G01N33/50 ,  C07H21/04 ,  A61K48/00 ,  C07K14/47

CPC分类号： C07K16/18 ,  C07K14/70503 ,  C07K14/82 ,  C12Q1/6827 ,  C12Q1/683 ,  C12Q1/6886 ,  C12Q2600/118 ,  G01N33/57419 ,  Y10S436/813 ,  Y10T436/143333

摘要： A new human gene termed DCC is disclosed. Methods and kits are provided for assessing mutations of the DCC gene in human tissues and body samples. Insertion, deletion, and point mutations in DCC are observed in human tumor cells. Normal tissues express DCC while most colorectal cancers do not. Loss of wild-type DCC genes is associated with neoplastic progression and a diminished life expectancy.

公开(公告)号：EP0698123A1

公开(公告)日：1996-02-28

申请号：EP94917285.0

申请日：1994-05-02

申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE ,  DE LA CHAPELLE, Albert

发明人： DE LA CHAPELLE, Albert ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15 ,  C07K14 ,  C12Q1 ,  A61K38

CPC分类号： C12Q1/683 ,  A61K38/00 ,  C07K14/82 ,  C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/156 ,  C12Q2600/172

摘要： Markers of chromosome 2 are associated with cancer predisposition, as shown by linkage analysis, in a significant fraction of families with a history of colon and other cancers. Tumors from these patients progressed through the same series of accumulated mutations in oncogenes and tumor suppressor genes found in non-familial cases, but showed no losses of heterozygosity for the linked chromosome 2 markers. DNA from the tumors (but not normal tissues) in most familial cases revealed a consistent and distinct abnormality: rearrangemnets in short repeated sequences throughout their genomes. This abnormality suggests that a large number of replication errors had occurred during tumor development. Methods are presented for detecting the presence of the gene which predisposes people to have a colon and other tumors and for utilizing this information for diagnostic, prognostic, and preventive purposes. DNA markers useful for such methods are also described.

公开(公告)号：EP0689606A1

公开(公告)日：1996-01-03

申请号：EP94911656.0

申请日：1994-03-21

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： HILL, David E. ,  JOHNSON, Karen A. ,  KINZLER, Kenneth W. ,  VOGELSTEIN, Bert

IPC分类号： G01N33 ,  C07K14 ,  C07K16 ,  C12N5 ,  C12N15 ,  C12P21 ,  C12R1

CPC分类号： C07K16/18 ,  C07K14/47 ,  C07K16/22 ,  C07K2319/00

摘要： Antibodies and assays employing them are taught which are useful for detecting the bulk of mutations which occur in the APC gene in familial adenomatous polyposis. The antibodies are specific for epitopes in the amino terminal or carboxy terminal portion of the protein. A variety of immunoassay formats are described which are all based on the observation that the bulk of the APC mutations which occur in familial adenomatous polyposis and sporadic colorectal carcinomas result in truncated APC proteins. Generally, either the size of APC proteins is determined or the relative binding of amino terminal-binding antibodies to carboxy terminal-binding antibodies is determined.

公开(公告)号：EP0551401B1

公开(公告)日：1995-11-02

申请号：EP91918778.1

申请日：1991-09-12

申请人： THE JOHNS HOPKINS UNIVERSITY ,  BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

发明人： FROST, Philip ,  VOGELSTEIN, Bert ,  CHERNAJOVSKY, Yuti ,  FEARON, Eric, R. ,  PARDOLL, Drew

IPC分类号： C12N15/85 ,  A61K48/00 ,  A61K35/12 ,  C12N5/10

CPC分类号： C07K14/005 ,  A61K35/13 ,  A61K39/0011 ,  A61K48/00 ,  C07K14/34 ,  C07K14/55 ,  C07K14/57 ,  C12N2710/16622 ,  C12N2760/16122

摘要： The invention provides a preparation of tumor cell lines containing an exogenous gene encoding a polypeptide that potentiates the immune response to the tumor, for example, interleukin-2. The invention includes methods for cancer therapy by immunization with the immunopotentiating tumor cell. The invention also provides methodology whereby one can selectively ablate in vitro and in vivo genetically altered cells. A preferred embodiment of this aspect of the invention includes a cell containing a first exogenous gene encoding an immunopotentiating polypeptide and a second exogenous gene encoding a "lethal" or "suicide" polypeptide, preferably under the control of an inducible promoter. Introduction of the second exogenous gene confers the ability to selectively kill the tumor cell by inducing a promoter in operative linkage to the gene encoding the lethal polypeptide to initiate transcription of the polypeptide. Diphtheria toxin or the thymidine kinase of Herpes simplex virus are exemplary lethal genes. An exemplary promoter employed is the 6-16 promoter, which is inducible with low levels of interferon. Methods for using the cells in cancer therapy are also provided.