EP0700436A1 - Gene de metastase de tumeur - Google Patents

Gene de metastase de tumeur

Info

Publication number
EP0700436A1
EP0700436A1 EP94916320A EP94916320A EP0700436A1 EP 0700436 A1 EP0700436 A1 EP 0700436A1 EP 94916320 A EP94916320 A EP 94916320A EP 94916320 A EP94916320 A EP 94916320A EP 0700436 A1 EP0700436 A1 EP 0700436A1
Authority
EP
European Patent Office
Prior art keywords
dna
seq
nucleic acid
sequence
sample
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94916320A
Other languages
German (de)
English (en)
Inventor
David Tarin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oxford University Innovation Ltd
Original Assignee
Oxford University Innovation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oxford University Innovation Ltd filed Critical Oxford University Innovation Ltd
Publication of EP0700436A1 publication Critical patent/EP0700436A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • tumours Metastatic spread of tumours from the site of primary growth to distant organs, where seedling tumours are formed by disseminated cells, is the most clinically important property of malignant tumours. It endows the community of tumour cells with the ability to survive surgical excision of the primary growth. Also, because metastases can themselves act as foci for further shedding and dissemination of tumour cells, this process forms the basis for a geometric increase in the impact of the tumour on the host and increasing difficulty in clinical management, because of the wide dispersal of the tumour burden. The magnitude of the effect of this phenomenon on human health can be appreciated by reference to the mortality statistics published by the Registrar General of the United Kingdom.
  • the fragment has been sequenced and c comparison of this information with entries in the
  • GenBank/EMBL DataBank indicates that it contains human DNA which has not been previously recorded. Further analysis of the sequence by computer programmes to detect coding regions as well as by Northern blotting and by reverse transcription-poly erase chain reaction (RT-PCR) techniques, has provided converging lines of evidence that parts of it are vigorously transcribed (expressed) in malignant human tumours and their metastases, but not comparably so in non-neoplastic tissue. The significance of this finding is that the sequence has the potential to be a valuable probe for the accurate assessment of the prognosis of patients with malignant tumours, by examination of a tiny biopsy sample or even a few cells obtained by fine needle aspiration, and thus to influence therapy. 5
  • the invention provides the 2858bp DNA whose sequence (SEQ ID NO: 1) is shown in the Figure.
  • the invention also provides a nucleic acid o which codes for a protein which is expressed in malignant human tumours and their metastases, which nucleic acid is selected from: the 2858bp DNA whose sequence (SEQ ID NO: 1) is shown in the figure, degenerated and allele variations thereof, fragments 5 thereof, longer DNA chains comprising any of these, and DNA which hybridises to any of these.
  • the nucleic acid can be incorporated into an expression vector, and the vector into a microorganism.
  • the expression vector and the transformed microorganism Q constitute further aspects of the invention.
  • the invention provides use of the defined nucleic acids or derivatives or fragments thereof for the identification, preparation or isolation of the nucleotide sequence or portions thereof coding for a protein which is expressed in malignant human tumours and their metastasis.
  • the inventor intends to proceed with blotting, PCR and library screening techniques, to search for related flanking sequences and cDNA clones. In this way, it is hoped to recover stretches of human DNA which are worth testing in functional assays to evaluate their metastatic inductive capability.
  • These experiments may include reintroduction of the defined expression vectors into non-metastatic tumour cell lines.
  • the invention also provides a method of investigating metastasis which method comprises obtaining a sample of cells, and analysing the sample for the nucleic acid of the 2858bp nucleic acid fragment or for a complementary RNA sequence.
  • This analysis may preferably involve the use of reverse transcriptase to form cDNA corresponding to RNA of the sample; amplifying the cDNA, e.g. by the polymerase chain reaction; and performing a hybridisation assay of the amplified DNA using as a hybridisation probe a fragment or the whole of the defined DNA.
  • Tne sample of cells may be a clinical sample of body fluid (e.g. blood, urine, sputum or stool) or body tissue (e.g. tumour tissue) of a patient.
  • the sample may be a histological section which is probed using a fluorescent or other labelled probe for mRNA corresponding to the 2858bp nucleic acid fragment.
  • GCG Computer Group
  • the GCG program CodonPreference was used to display potential open reading frames (i.e. stretches of sequence without a frame stop codon) ; and to predict the likely coding regions, based on the degree of codon bias shown towards a reference codon usage set of highly expressed human genes.
  • the level of GC bias and codon usage bias were seen that corresponded to possible open reading frames (ORFs). Among the most notable is the region from approximately bases 1650 to 1800 in the 2nd reading frame of the reverse strand.
  • Grail predicted three possible exons, one in the forward strand in frame 2 (between bases 536 and 942) and two in the reverse strand, in frames 1 (between bases 2143 and 2398) and 2 (between bases 1625 and 1907). These three regions all corresponded to exons predicted by GenelD and also to donor and acceptor sites found by NetGene (see Table 2) . All three exons fell within regions of higher than expected codon preference and GC bias as predicted by CodonPreference analysis. The region around the possible exon in the second frame of the reverse strand was therefore the first one chosen for further study, being the one with the highest probability of being a coding region.
  • the whole DNA sequence was also examined for potential transcription factor coding domains and binding sites by searching against the release 6.3 of the Ghosh database using GCG FindPatterns. Although some tentative matches were found a detailed study of the compositions of these and their locations in the three reading frames indicated that these were all very unlikely to be true transcription factor coding regions.
  • the translated sequence was also searched against release 10.1 of the Prosite database to search for potential DNA binding regions using the GCG program Motifs, but no homology to previously recorded regions could be identified.
  • RNA extracted from cell lines and solid tissue samples was reverse transcribed with viral reverse transcriptase and the cDNA so obtained specifically amplified with primers P1 and P4 designed to anneal to the outer ends of the putative coding region identified by computer analysis between base 951 and 1233 on the reverse strand of the 2858 base pair complete sequence. Samples were also amplified using primers P2 and P4. The PCR products were separated by gel electrophoresis in 1.6% agarose and stained with ethidium bromide for viewing in a U-V transilluminator.
  • PCR cycle parameters were as follows: 1 period at 94'C for 4 minutes, followed by 1 period at 82'C for 2 minutes, during which time the Taq enzyme was added, followed by 30 cycles of 92'C for 30 seconds, 60°C for 30 seconds and 70°C for 2 minutes.
  • Control studies to monitor the quality of mRNA and the success of cDNA synthesis in the RT-PCR techniques were conducted using 2 ⁇ l aliquots from the same samples amplified with primers to the human ⁇ - actin gene (Clontech Laboratorie Inc., Palo Alto, CA) .
  • Footnote ⁇ -actin expression was determined in an aliquot from each sample as a control to evaluate quality of mRNA obtained from the sample TABLE 2
  • MOLECULE TYPE DNA (genomic)
  • AAACAGCTGC CCCCCACACA CACACACAGG TCCCCCATTC AGTTGGTACC TTTTTGATAG 4
  • CAAGACTCTT CCTCCTCAGA ACCTGGGCGG GAAGAATTGC AAGGTAGGGG TAGACAGACT
  • CTAGAGTCAC ACAAATCTAA CAGAGCTGGG TACCTCTCAG AGATGGCTGC TAAGGTGGTG
  • CTCCACCCTT CTCCTTGTTT GTTTTGTTTT GTTTTTTCTC TGTGTAGCTC TGGCTGTCCT 1
  • CAAAATCATA AACTTACTCA AAACATTATG AAAATAGTTT GCACGAACTT TCTTTGTTGT 1
  • CTCTGCCTCC CAGGTGCTGG TCTACAGGGG AAGATTATGT TGTCCTTGGG TATGTCCTTA 2
  • MOLECULE TYPE DNA (genomic)
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 2
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Pathology (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Hospice & Palliative Care (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un fragment d'ADN de 2858pb (SEQ ID NO:1) codant pour une protéine exprimée dans des tumeurs humaines malignes, ainsi que dans leurs métastases. Le fragment d'ADN est efficace dans l'établissement d'un diagnostic ou dans la détermination de l'évolution d'une métastase chez un patient.
EP94916320A 1993-05-28 1994-05-27 Gene de metastase de tumeur Withdrawn EP0700436A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939311130A GB9311130D0 (en) 1993-05-28 1993-05-28 Tumor metastasis gene
GB9311130 1993-05-28
PCT/GB1994/001160 WO1994028129A2 (fr) 1993-05-28 1994-05-27 Gene de metastase de tumeur

Publications (1)

Publication Number Publication Date
EP0700436A1 true EP0700436A1 (fr) 1996-03-13

Family

ID=10736338

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94916320A Withdrawn EP0700436A1 (fr) 1993-05-28 1994-05-27 Gene de metastase de tumeur

Country Status (6)

Country Link
EP (1) EP0700436A1 (fr)
JP (1) JPH09504682A (fr)
AU (1) AU6802294A (fr)
CA (1) CA2149633A1 (fr)
GB (1) GB9311130D0 (fr)
WO (1) WO1994028129A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997018454A2 (fr) * 1995-11-16 1997-05-22 Baylor College Of Medicine Procede d'identification de sequences metastasiques
USRE38490E1 (en) 1995-11-16 2004-04-06 Baylor College Of Medicine Method for identifying metastatic sequences
US5783182A (en) * 1996-01-30 1998-07-21 Baylor College Of Medicine Method for identifying metastatic sequences
US6875429B1 (en) * 1996-01-10 2005-04-05 University Of Liverpool Metastasis inducing DNA's
USRE38392E1 (en) 1996-01-30 2004-01-20 Baylor College Of Medicine Method for identifying metastatic sequences
AU734476B2 (en) 1997-11-05 2001-06-14 Baylor College Of Medicine Sequences for targeting metastatic cells
US6545139B1 (en) 1998-03-13 2003-04-08 Baylor College Of Medicine DNA sequence encoding the p99 gene and kits for the detection of neoplasia
US7462491B2 (en) 2002-01-31 2008-12-09 Baylor College Of Medicine Methods and compositions for diagnosis and monitoring of prostate cancer progression by detection of serum caveolin

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4064113A (en) * 1973-06-15 1977-12-20 Alelio Gaetano F D Aminophthalic anhydride copolymers
US4131730A (en) * 1975-05-12 1978-12-26 Alelio Gaetano F D Modified polyamic acid from aminophthalic acid anhydride and dianhydride
JPS61143435A (ja) * 1984-12-15 1986-07-01 Nitto Electric Ind Co Ltd 耐湿性ポリイミド
JPS6213436A (ja) * 1985-07-11 1987-01-22 Nitto Electric Ind Co Ltd 無色透明なポリイミド成形体
JPS61226732A (ja) * 1985-03-30 1986-10-08 Nitto Electric Ind Co Ltd 液晶表示素子
US5049662A (en) * 1987-10-13 1991-09-17 The United States Of America As Represented By The Department Of Health And Human Services Kit for diagnosing cancer metastatic potential
KR930005151B1 (ko) * 1990-05-15 1993-06-16 재단법인 한국화학연구소 폴리에테르이미드이미드수지와 그 제조방법
ATE152629T1 (de) * 1990-07-09 1997-05-15 Res Corp Technologies Inc Diagnose von krebs-metastasen durch das mts-1 gen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9428129A2 *

Also Published As

Publication number Publication date
AU6802294A (en) 1994-12-20
WO1994028129A2 (fr) 1994-12-08
GB9311130D0 (en) 1993-07-14
WO1994028129A3 (fr) 1995-02-02
JPH09504682A (ja) 1997-05-13
CA2149633A1 (fr) 1994-12-08

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