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WO1998000561A1 - Expression du gene reg dans un tissu cancereux - Google Patents

Expression du gene reg dans un tissu cancereux Download PDF

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Publication number
WO1998000561A1
WO1998000561A1 PCT/GB1997/001739 GB9701739W WO9800561A1 WO 1998000561 A1 WO1998000561 A1 WO 1998000561A1 GB 9701739 W GB9701739 W GB 9701739W WO 9800561 A1 WO9800561 A1 WO 9800561A1
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WO
WIPO (PCT)
Prior art keywords
reg
gene
assay system
cancer
tissue
Prior art date
Application number
PCT/GB1997/001739
Other languages
English (en)
Inventor
Alexander Fred Markham
Pierre John Guillou
Original Assignee
Zeneca Limited
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 Zeneca Limited filed Critical Zeneca Limited
Priority to AU33499/97A priority Critical patent/AU3349997A/en
Priority to JP10503917A priority patent/JP2000513936A/ja
Priority to EP97929377A priority patent/EP0912762A1/fr
Publication of WO1998000561A1 publication Critical patent/WO1998000561A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the invention relates to a method and/or marker for determining the aggressive nature of cancer tissue for use particularly, but not exclusively, for diagnostic, prognostic or drug screening purposes; and a kit for use therefor.
  • the invention is thought to have particular application in determining a predisposition towards and/or the aggressive nature of gastrointestinal, pancreatic, colorectal, prostate cancers.
  • the invention should be limited thereto, rather, we consider that the invention has wide application in a determination of the aggressive nature of any type of cancer tissue.
  • Dukes' C disease Studies have shown an advantage in administration of adjuvant chemotherapy using 5-fluorouracil and a biological modifier of 5-fluorouracil activity. It is, however, unclear which of those patients with earlier stage diseases (Dukes' stages A and B) would benefit from adjuvant chemotherapy. Whilst the majority of patients with early stage disease are likely to survive free of disease recurrence for five years, a small but significant proportion of these suffer disease relapse and die of the effect of their cancers. It would therefore be highly desirable to develop a method of predicting those patients with early stage disease who are likely to relapse in order to offer adjuvant chemotherapy to this selected group.
  • such a marker would also be of significant benefit in determining the efficacy of cancer drugs. This is because individuals identified as either positive or negative for the marker could be suitably selected for clinical trials. Thus, the data from such trials would not be compromised by the use of a distorted sampling population, in other words poor results could be assessed having regard to the predicted aggressive nature of the disease to be treated.
  • the pancreas regenerating gene (REG), identified by Terazono et ⁇ (1) in 1988, is expressed in regenerating pancreatic islet cells in the rat but not i normal islet cells.
  • the human homologue to rat REG cDNA in pancreas encodes a 166 amino acid protein with a signal sequence.
  • This sequence derived from REG cDNA contains a previously described 144 amino acid sequence of pancreatic stone protein (PSP) (2) and the partially-determined 45 amino acid sequence of pancreatic stone protein.' 31
  • the human REG gene has been mapped to chromosome 2pl2. (4, 5) It is a pleiotropic gene with a role in modulating cell replication growth and maturation.
  • the protein product, lithostathine is secreted by the normal exocrine pancreas and inhibits the growth of calcium carbonate crystals. Levels of this protein in pancreatic juice have been found to be reduced in chronic pancreatitis.
  • the PCR reaction amplifies cDNA for the gene REG which is constitutively expressed in pancreatic acinar tissue and encodes for the secreted protein lithostathine. Moreover, we have shown that REG gene products are present in peritoneal washing from patients with pancreatic cancer.
  • products of the REG gene serve as markers for not only establishing the tendency towards, but also the aggressive nature of cancer tissue.
  • a method for determining a tendency of a tissue to become cancerous or the aggressive nature of cancer tissue comprising examining said tissue and/or fluid associated with same to identify a product of REG gene transcription and/or translation.
  • said investigation involves the identification of REG mRNA alternatively, or in addition, it involves a determination of the REG gene protein.
  • antibodies monoclonal or polyclonal, may be used in order to bind to said REG protein.
  • additional antibodies may be used to amplify the nature of the reaction and/or antibodies tagged with suitable labels may also be used.
  • a blood sample may be taken and the amount of REG gene product determined and ideally compared with normal levels. Once this is done an elevated level of REG gene product in an individual suffering from, or known to have suffered from, cancer would be indicative of the existence of, or recurrence of, an aggressive cancer, respectively, and so appropriate action could be taken.
  • the use of the REG gene, and more particularly, a product thereof for the determination of the aggressive nature of cancer tissue is provided.
  • a screening procedure for determining the efficacy of a selected therapeutic comprising;
  • kits for determining the aggressive nature of cancer tissue comprising means suitable for identifying transcription and/or translation of the REG gene.
  • Figure 1 shows the correlation between the currently used Dukes' classification and REG gene mRNA expression.
  • Figure 2 shows tumour recurrence data for individuals that are REG gene positive and REG gene negative.
  • Figure 3 is a graph showing the survival rate of individuals who are REG gene positive and REG gene negative.
  • Figure 4 shows two years survival data for individuals who are REG gene positive and REG gene negative.
  • Figure 5 shows cancer specific survival rate for individuals who are REG gene positive and REG gene negative.
  • Figure 6 shows survival in patients with REG-positive tumours of the colon or rectum with and without REG mRNA detected in bone marrow aspirates at the time of surgery.
  • Figure 7 shows a disease-free survival in patients with REG-positive tumours of the colon or rectum with and without REG mRNA detected in bone marrow aspirates at the time of potentially curative surgery.
  • Figures 8 and 9 shows the expression of the REG gene in both cancer tissue and tissue at a varying distance therefrom (i.e. 2, 4, 6 cm) and in normal- appearing mucosa (n ) situated at the margin.
  • Figure 10 shows expression of REG mRNA in prostatic biopsy material (duplicated results).
  • Ulcerative Colitis Figure 1 1 shows REG expression in mucosal biopsies in active inflammatory bowel disease, and in quiescent-appearing mucosa.
  • REG gene products as suitable markers for determining the aggressive nature of cancer tissue was identified having regard to the following experiments.
  • RNA pellet resuspended 20 l of water, containing lmmol DTT and 1 unit per ⁇ l RNAsin.
  • PCR for REG cDNA was carried out only after satisfactory results were obtained from PCR reactions instigated to detect DNA contamination of RNA samples, using heat shock protein primers and cDNA formation using G3PDH primers.
  • Primers spanning introns were devised to amplify a 263bp product of REG cDNA (REG upper dAACATGAATTCGGGCAACC; REG lower dGGCACATCCTTCCATTTCT).
  • REG primers and template (l ⁇ l RT reaction product) in a final volume of lO ⁇ l were overlaid with mineral oil and heated to 95° C for a hot start PCR.
  • the reaction was initiated by adding lO ⁇ l of 2 x PCR reaction mix containing 10 x Taq buffer (2 ⁇ l), magnesium chloride (2mmoI), DNTPs (0.2mmol each) and Taq polymerase (2 units).
  • Defrosted slides were fixed in 70% ethanol for 10 minutes prior to immunostaining using the strepatavidin-biotin method with fast red as chromagen.
  • Non-specific staining was minimised by initial pre-incubation with normal rabbit serum. Excess serum was removed and the primary anti- epithelial monoclonal antibody Ber-EP4 applied for 30 minutes at room temperature. Following washing and further rabbit serum blockade, a rabbit anti-mouse biotinylated conjugate was applied for 30 minutes(Dako UK). Following further washing and brief incubation with Tris buffer, alkaline phosphatase conjugated streptavidin was added for 30 minutes (Dako UK).
  • RNA pellet was resuspended in 20 ⁇ l of water containing ImM dithiothreitol and lU/ ⁇ l RNAsin (Promega, Southampton).
  • RNA (lO ⁇ l) was reverse transcribed in a 20 ⁇ l reaction using 120U MMLV- RT (Promega) 0.5 ⁇ g oligo (dT), ImM each dNTP 20U RNAsin , in IX reverse transcription buffer with 3mM MgCl 2 , at 42 ° C for 1 hour followed by a five minute heat inactivation period at 95 ° C. All cDNA samples underwent amplification using primers for a constitutively expressed gene
  • Fresh mucosa specimens were obtained and snap frozen direct from surgical specimens at resection of histologically proven colorectal cancer. Samples were obtained 6,4 and 2 cm proximal to the tumour edge, in addition to tumour edge itself and the proximal resection margin of the surgical specimen, and stored at -80C. RNA extraction and RT-PCR were carried out as described above for bone marrow investigations in patients with colorectal cancer.
  • tumour specimens had strongly positive bands indicating REG cDNA following the PCR reaction. 17 tumour specimens had very weak or absent bands. In four cases apparently normal mucosa samples from surgical resection specimens contained REG cDNA, but in each case only in association with a REG expressing tumour in the same specimen ( Figure 1, Figure 2).
  • Ectopic expression of the REG gene was identified in normal-appearing mucosa 2cm from REG expressing colorectal cancers in 10 of 13 cases. Expression of REG in both carcinomas and normal appearing tissue 2cm away was significantly more common than in tissue from the proximal resection margin or 6cm from the tumour edge ( Figures 8 and 9).
  • REG mRNA in bone marrow may add a further degree of accuracy to prognostication in colorectal cancer. It is also of interest that a high proportion of node-negative tumours expressing REG presented with REG mRNA present in bone marrow, supporting the view that REG expression may be a biomarker of aggressive behaviour in these tumours. Histopathological diagnosis of a 'node-negative ' status may therefore be an unreliable indicator of lack of metastatic disease.
  • Bone marrow was aspirated from two sites in 15 consenting patients undergoing general anaesthesia with a diagnosis of pancreatic cancer based upon either cross sectional imaging using CT or MRI, or atypical cells obtained by brushing at ERCP or fine needle aspiration cytology. In addition, bone marrow was obtained from three patients with benign pancreatic pathology undergoing anaesthesia.
  • Immunocytochemistry was carried out on duplicate slides from 15 patients with histologically proven adenocarcinoma of the pancreas (10) and duodenum (2) and from a control group of four patients with benign pancreatic disease.
  • tumour cells were detected in bone marrow by immunocytochemistry in one of 10 cases, and one of two duodenal carcinomas had bone marrow micrometastases. None of the four control cases had positively staining cells present.
  • Bone marrow from patients with pancreatic and ampullary tumours contained REG mRNA in 3 of 10 cases.
  • This RT-PCR-positive group included the patient with positive marrow demonstrated by immunocytochemistry. The implication is that RT-PCR may well be more sensitive for the detection of micrometastases than microscopy-based techniques alone. No REG mRNA was present in the marrow of either patient with duodenal carcinoma or any of the non-malignant control cases.
  • pancreatic cancer The poor overall prognosis of pancreatic cancer is partially due to the frequently late presentation of the disease and hence advanced stage at the time when surgery is considered.
  • Our group of pancreatic cancer patients consists solely of those patients with cross sectional imaging results suggesting that tumour resection might be possible, and this may explain why the rate of micrometastases detected by immunocytochemistry is somewhat lower than reported elsewhere .
  • the presence of micrometastases (detected by histology) in the bone marrow of one of the cases of duodenal carcinoma was associated with an advanced tumour that required operative intervention for gastric outlet obstruction. This suggests that duodenal cancers may not usually express REG mRNA.
  • REG RT-PCR may be a more sensitive method of detection of small numbers of pancreatic cells in bone marrow than immunocytochemistry.
  • REG is constitutively expressed by the acinar cells, and in some malignant tumours of the ductal epithelium of the pancreas. The majority of pancreatic carcinomas arise from the ductal epithelium.
  • REG mRNA was identified by RT-PCR, as previously described, in 40% of these cases.
  • pancreatic cancer Potential applications of peritoneal disease status in pancreatic cancer revolve around the ability of viable tumour cells in the peritoneal cavity to predict early relapse following potentially curative surgery.
  • the advantages of such prediction in pancreatic cancer would accrue from better targeting of an aggressive surgical approach. This may potentially reduce the number of aggressive procedures carried out on patients with a poor prognosis and limited survival potential following diagnosis in whom a palliative approach would be more appropriate. Additionally it may identify the cohort of patients in whom the investment of time and resources by both patient and surgeon in attempting cure would be fully justified.
  • Prostate cancer is a notoriously heterogeneous disease, with the majority of tumours being small and multifocal. Sampling error may therefore influence results based upon biopsy specimens leading to false negative results.
  • the expression of the proliferation-associated gene REG in prostate cancer may be associated with the process of oncogenesis in this organ. Most interesting is the clinical entity of benign prostatic hypertrophy (BPH), a very common condition in men, some of whom go on to develop invasive carcinoma of the prostate. REG expression could be used as a potential biomarker of malignant potential in BPH.
  • BPH benign prostatic hypertrophy
  • endoscopically obtained mucosal biopsies were snap frozen and stored at - 80C until analysis from X patients with active inflammatory bowel disease. In all 16 patients, further endoscopic biopsies were obtained on later occasions at which time the naked eye appearance of the mucosa, as being either actively inflamed or in remission, was noted. Subsequent ..RNA extraction and RT-PCR was carried out as described above.
  • REG gene expression is a common feature among colorectal carcinomas but it is a far less frequent feature of normal colonic mucosa, and then only in association with a local tumour.
  • the presence of REG gene expression in association with REG expressing tumours raises the possibility of a field change surrounding the neoplasm.
  • REG gene expression needs to be a strong predictor of clinical outcome such as this must be taken into account when planning and interpreting studies concerning the efficacy of adjuvant chemotherapy. Forthwith REG status should be established before accepting the similarity of two arms of randomised chemotherapy trials if bias is not to be introduced.
  • REG gene expression is also a common, features of other cancers such as pancreatic cancer where, again, the accurate prediction of post-operative outcome is a worth while end and the place of immunocytochemistry in refining this has been demonstrated in numerous tumours of the gastrointestinal tract. Increases in sensitivity using methodology such as RT- PCR offer the possibility of further identifying those patients most at risk of treatment failure, identification of which will have important implications in the evaluation and implementation for adjuvant therapy for pancreatic cancer. This is also true of prostrate cancer where REG expression can be used as a marker for malignant tissue. Additionally, REG expression can also be used to predict a tendency towards the development of malignancy in diseased conditions, such as ulcerative colitis, which are known to progress in this manner. In conclusion, the assay of REG gene expression may be of general utility in assessing prognosis in cancer patients at presentation and in guiding the choice of aggressive or less potentially toxic treatment modalities.

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  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
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  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un marqueur permettant de déterminer une tendance au développement cancéreux et/ou la nature agressive d'un tissu cancéreux en vue de déterminer un pronostic et une intervention/un traitement approprié(e). De manière plus spécifique, l'invention concerne une recherche de produits du gène REG, à savoir le gène lithostathine de protéine pancréatique (REG.)
PCT/GB1997/001739 1996-06-28 1997-06-30 Expression du gene reg dans un tissu cancereux WO1998000561A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU33499/97A AU3349997A (en) 1996-06-28 1997-06-30 Reg gene expression in cancer tissue
JP10503917A JP2000513936A (ja) 1996-06-28 1997-06-30 ガン組織におけるｒｅｇ遺伝子発現
EP97929377A EP0912762A1 (fr) 1996-06-28 1997-06-30 Expression du gene reg dans un tissu cancereux

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9613629.6 1996-06-28
GBGB9613629.6A GB9613629D0 (en) 1996-06-28 1996-06-28 Reg gene expression in cancer tissue

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WO1998000561A1 true WO1998000561A1 (fr) 1998-01-08

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JP (1) JP2000513936A (fr)
AU (1) AU3349997A (fr)
CA (1) CA2252464A1 (fr)
GB (1) GB9613629D0 (fr)
WO (1) WO1998000561A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001847A1 (fr) * 1998-07-01 2000-01-13 University Of Leeds Marqueur combine du cancer
WO2000014283A3 (fr) * 1998-09-04 2000-06-02 Univ Washington Genes marqueurs pour lesions chroniques des muqueuses
WO2004092352A3 (fr) * 2003-04-14 2006-02-02 Univ Washington Rupture de la voie reg
WO2009030456A1 (fr) * 2007-09-07 2009-03-12 Universität Zürich Procédé d'analyse pour prévision d'une septicémie chez les humains

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0369797A2 (fr) * 1988-11-16 1990-05-23 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Anticorps monoclonal reconnaissant la protéine Reg
GB2260811A (en) * 1991-10-23 1993-04-28 Yorkshire Cancer Research Camp Diagnosis of malignant tumours by mRNA detection

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0369797A2 (fr) * 1988-11-16 1990-05-23 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Anticorps monoclonal reconnaissant la protéine Reg
GB2260811A (en) * 1991-10-23 1993-04-28 Yorkshire Cancer Research Camp Diagnosis of malignant tumours by mRNA detection

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KIMURA N.ET AL.,: "Expression of human regenerating gene mRNA and its product in normal and neoplastic human pancreas", CANCER, vol. 70, no. 7, - 1 October 1992 (1992-10-01), pages 1857 - 1863, XP002044998 *
PERFETTI P. ET AL: "Regenerating (reg) and insulin genes are expressed in prepancreatic mouse embryos", J. MOLECULAR ENDOCRINOLOGY, XP002044999 *
WATANABE T. ET AL: "Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissue", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 265, no. 13, 5 May 1990 (1990-05-05), pages 7432 - 7439, XP000126179 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001847A1 (fr) * 1998-07-01 2000-01-13 University Of Leeds Marqueur combine du cancer
WO2000014283A3 (fr) * 1998-09-04 2000-06-02 Univ Washington Genes marqueurs pour lesions chroniques des muqueuses
US6228585B1 (en) 1998-09-04 2001-05-08 Washington University Gene markers for chronic mucosal injury
WO2004092352A3 (fr) * 2003-04-14 2006-02-02 Univ Washington Rupture de la voie reg
WO2009030456A1 (fr) * 2007-09-07 2009-03-12 Universität Zürich Procédé d'analyse pour prévision d'une septicémie chez les humains
US8435755B2 (en) 2007-09-07 2013-05-07 Universitaet Zuerich Method for assaying sepsis in humans
AU2008295046B2 (en) * 2007-09-07 2013-08-01 Universitat Zurich Method for assaying sepsis in humans
US9857381B2 (en) 2007-09-07 2018-01-02 Universitaet Zuerich Method for assaying sepsis in humans

Also Published As

Publication number Publication date
AU3349997A (en) 1998-01-21
GB9613629D0 (en) 1996-08-28
CA2252464A1 (fr) 1998-01-08
EP0912762A1 (fr) 1999-05-06
JP2000513936A (ja) 2000-10-24

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