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WO2000001847A1 - Marqueur combine du cancer - Google Patents

Marqueur combine du cancer Download PDF

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Publication number
WO2000001847A1
WO2000001847A1 PCT/GB1999/001877 GB9901877W WO0001847A1 WO 2000001847 A1 WO2000001847 A1 WO 2000001847A1 GB 9901877 W GB9901877 W GB 9901877W WO 0001847 A1 WO0001847 A1 WO 0001847A1
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WO
WIPO (PCT)
Prior art keywords
reg
survivin
tissue
cancer
genes
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PCT/GB1999/001877
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English (en)
Inventor
Alexander Fred Markham
Pierre John Guillou
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University Of Leeds
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 University Of Leeds filed Critical University Of Leeds
Priority to AU45177/99A priority Critical patent/AU4517799A/en
Publication of WO2000001847A1 publication Critical patent/WO2000001847A1/fr

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    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/118—Prognosis of disease development

Definitions

  • the present 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 therewith.
  • the present invention is thought to have particular application in determining a predisposition towards and/or the aggressive nature of cancers such as gastrointestinal, pancreatic, colorectal, other gastrointestinal and prostate cancers and in the determination of the need for adjuvant therapy. Moreover, it is not intended that the present invention should be limited to the aforementioned tumour sites or tumour types, rather we consider that the invention has wide application in determining the aggressiveness of any type of cancer tissue at any site.
  • Reference herein to an aggressive cancer is intended to mean the likelihood of a cancer recurring at the same site or at a secondary/remote site following primary curative treatment and/or surgery.
  • Colorectal cancer is the second most common cancer in the UK after lung cancer. There are approximately 30,000 new diagnoses in the UK per annum and approximately 300,000 cases diagnosed per annum in the major developed countries i.e. Japan, Europe and the USA. According to one source, at least 50% of the Western population develops a colorectal neoplasm by the age of 70, and in about 1 in 10 of these individuals progression to malignancy ensues (1).
  • TAP' familial adenomatous polyposis
  • HNPCC Hereditary non-polyposis colon cancer
  • a number of techniques have been developed in order to try and predict the aggressive nature of cancer tissue and the accepted practice for such an assessment in colorectal cancer involves subjecting a biopsy or resection specimen to routine histo- pathological staging using what is known as the Dukes' classification. This classification involves an examination of the specimen in order to determine principally the penetrative nature of a tumour. Essentially, there are four classifications A, B, C and D.
  • Dukes' A is characterised in that tumours have been confined to within the bowel wall, and are typically cancers that only affect the innermost lining (epithelial layer) of the colon or rectum.
  • Dukes' A is an early stage of the disease and is usually eradicated by surgery. Patients have a typical five year survival rate of between 90- 95% following surgery.
  • Dukes' B disease is characterised in that it is further advanced cancer than Dukes' A, the cancer having grown into the muscle layer of the colon or rectum so that it has at least partially penetrated the bowel wall.
  • patients are treated firstly by surgery and it is debatable whether there is immediate need for additional adjuvant therapy.
  • the five year survival rate for combined sub-populations of Dukes' B colorectal cancer is between 60-65%. There is currently no practical method available to discriminate between possible sub-types of Dukes' B disease.
  • Dukes' C cancer is characterised in that tumours have spread to at least one local lymph node and is further characterised in that the disease is more advanced than Dukes' B stage, therefore requiring additional therapy to surgery, such as chemotherapy and/or radiotherapy.
  • the typical five year survival is less than 50%.
  • Dukes' C disease some studies have shown an advantage in the administration of adjuvant therapy.
  • Dukes' D disease is characterised in that the cancer has spread to a distant site(s) in the body such as the liver or lung and is a disseminated metastatic disease.
  • the five year survival rate is less than 10% and adjuvant therapy is often not given because the disease is too advanced for any realistic expectation of control.
  • a further advantage associated with the identification of a suitable marker for determining not only the aggressive nature of gastrointestinal cancers but also other cancers would be to allow significant developments in the treatment of cancer patients.
  • the successful identification of markers which provide prognostic data over and above that of conventional histopathology staging may modify decisions about adjuvant therapy in patients with a variety of different cancers including colorectal cancer.
  • such a marker would also be of significant benefit in determining the efficacy of any new cancer drug. This is because individuals identified as either positive or negative for the markers 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 and the genuine efficacy of the drug could be more accurately determined.
  • the first marker gene is associated with cellular regeneration and the second marker gene is associated with inhibition of programmed cell death.
  • these two markers are the pancreas regenerating gene (REG) (Accession No J05412) in combination with the anti- apoptosis gene, Survivin (Accession No U75285).
  • REG pancreas regenerating gene
  • a human gene of the IAP gene family termed Survivin, encoding a structurally unique apoptosis inhibitor has been shown to be present during foetal development but is undetectable in terminally differentiated adult tissues (2). However, the gene, which is located on chromosome 17q25 does become expressed in transformed cell lines and in most common human cancers in vivo (3). Further data suggests that expression of Survivin in mouse embryos indicates a role for apoptosis inhibitors in morphogenesis and that the IAP protein
  • Survivin is important in developmentally regulated mechanisms of tissue and organ differentiation. Most recently the anti-apoptosis gene Survivin has been implicated in the aggressive nature of neuroblastomas as defined by the Shimada classification (4).
  • Human REG gene has been located on chromosome 2pl2 and is a pleiotrophic gene with a role in modulating cell replication, growth and maturation (5). It encodes the secreted protein lithostathine. Low levels of said protein have been observed in the pancreatic juice of individuals suffering from chronic pancreatitis (6). Additionally, WO 98/00561 discloses that REG gene expression is a common feature among colorectal carcinomas but is a far less frequent feature of normal colonic mucosa, and then only in association with a local tumour.
  • 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 therewith, so as to identify a product of, in combination, REG and Survivin gene transcripts and/or translation products.
  • said investigation involves identification of, in combination, REG and Survivin rt RNAs, alternatively or in addition, it involves determination of, in combination, Survivin and REG proteins.
  • the proteins are to be determined by the use of antibodies, monoclonal or polyclonal, said antibodies may be used in order to bind to, in combination, said REG and Survivin proteins.
  • 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 in combination with Survivin gene product determined and ideally compared with normal levels. Once this is done, an elevated level of both REG and Survivin gene products 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.
  • a screening procedure for determining the efficacy of a selected therapeutic comprising:
  • REG and Survivin gene positive individuals whose cancers are expressing in combination both the REG and Survivin genes, termed REG and Survivin gene positive, will be selected. Conversely, individuals who do not express said genes will not be selected. However, in some instances a mixed population of individuals may be selected according to the requirements of the screening program.
  • kits for determining the aggressive nature of cancer tissue comprising means suitable for identifying transcripts and/or translation products of, in combination the REG and Survivin genes.
  • Table 1 represents patient characteristics based on expression of Survivin.
  • Figure 1 represents overall survival stratified by Dukes' stages.
  • Figure 2 represents expression of Survivin as a determinant of overall survival in patients with colorectal cancer (Dukes' stages A, B, C and D).
  • Figure 3 represents Survivin as a determinant of prognosis in patients with Dukes' stage B colorectal cancer
  • Figure 4 represents survival of patients with Dukes' B CRC as a function of their tumour's Survivin-REG co-expression profile.
  • Human colorectal carcinoma (LoVo, COLO 205, COLO 320, SW480, SW948 and HT29), gastric carcinoma (MKN-49 and KATO-III), pancreatic carcinoma (Mia-Pa- Ca and Panel), hepatocellular carcinoma (HepG2) and oesophageal carcinoma (OE- 19) cell lines were obtained from the European Cell Culture Bank. All cell lines were maintained in appropriate media supplemented with 10% fetal calf serum and antibiotics in a 5% carbon dioxide incubator at 37°C.
  • Biopsies of non-ulcerated tumour margin were obtained, immediately following large bowel resection for primary, single, sporadic colorectal carcinoma (CRC), from 144 patients who underwent operations. Normal colonic mucosa from the distal margin of the freshly resected specimen was available in 84 cases. Cryostat blocks were prepared from all biopsies, snap frozen in liquid nitrogen and stored at -80°C until examination. The remainder of the sample was fixed in 10% formaldehyde solution for histopathological examination. Pathological classification was conducted according to Turnbull's modification of Dukes' staging system, as shown in Table 1.
  • Cryostat sections were cut frozen tissue blocks to confirm by histopathology the presence of tumour in malignant tissues (or the absence of tumour in normal tissue).
  • Small samples ⁇ 10 mg of mucosa and tumour were taken from the frozen tissue blocks, ground to powder in liquid nitrogen, and immediately suspended in 1 ml of Catrimox-14TM cationic surfactant solution (Iowa Biotechnology Corp, Iowa, USA), as previously described (6).
  • Thawed cell-lines were also suspended in the same solution. Particulate remains were allowed to settle for five minutes and the supernatants aspirated into a fresh tube for further processing. The supernatant was centrifuged for five minutes at 1000 x g, forming a detergent-bound RNA pellet.
  • RNA pellet was resuspended in 1 ml of 2 M lithium chloride (LiCl) and then sedimented at 10000 x g for 5 minutes. Three cycles of washing and sedimentation in 2 M LiCl were performed, followed by a final wash with 70% ethanol at 4°C. Following centrifugation at 10000 x g for five minutes the ethanol was discarded and the pellet vacuum-dried for 30 minutes.
  • the RNA pellet was resuspended in 20 ⁇ l of DEPC-treated sterile water containing 1 mM dithiothreitol and 1 U/ ⁇ l RNAsin (Promega). The absence of contaminating genomic DNA was confirmed by PCR using intronic primers for heat-shock protein 70 (Accession number Ml 1717; primers at positions 281...304 and 485...462 bp).
  • RNA (10 ⁇ l of the above solution) was reverse transcribed in a 20 ⁇ l reaction using 120 U MMLV-reverse transcriptase (RT) (Promega), 1 mM of each dNTP, 0.5 ⁇ g oligo(dT)j 5 and 20 U RNAsin in a 1 x RT buffer with 3mM magnesium chloride.
  • RT MMLV-reverse transcriptase
  • the reaction mixture was incubated at 42°C for one hour followed by 95°C for 5 minutes.
  • all samples were subjected to PCR amplification with primers specific for the house-keeping gene glyceraldehye-3 -phosphate dehydrogenase.
  • Intron-spanning primers were designed to amplify a 338 bp product of Survivin cDNA (Accession number U75285).
  • the oligonucleotide sequences were 5' - dGGA CCA CCG CAT CTC TAC AT - 3' (forward) positions 2855..2874 bp in exon 1 ; and 5' - dGCA CTT TCT TCG CAG TTT CC - 3' (reverse), positions 11990..12009 in exon 4.
  • a BLAST search was performed to confirm that these primers were specific for Survivin.
  • PCR reaction was carried out in a final volume of 25 ⁇ l containing l ⁇ l cDNA, 20 pmol of each oligonucleotide primer, 2mM magnesium chloride, 0.625 U Taq DNA polymerase and 0.2mM of each dNTP. Forty cycles of PCR amplification were performed in a DNA Thermal Cycler (MJ Research Inc) with denaturing at 95 °C for one minute, annealing at 55°C for one minute and extension at 72°C for one minute. PCR products were size fractionated on 2% agarose gels in Tris acetate ethylenediaminetetraacetic acid buffer at 150 V for 20 minutes and visualised with ethidium bromide stain under ultra-violet light. A 100 bp DNA ladder (GIBCO-BRL) was used as a molecular weight marker on each gel.
  • REG RNA (lO ⁇ l) was reverse transcribed in a 20 ⁇ l reaction using 120U MMLV-RT (Promega) 0.5 ⁇ g oligo (dT), ImM each dNTP 2OU RNAsin, in lx 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 (glyceraldehyde-3 -phosphate dehydrogenase), to confirm the consistency of RNA extraction and reverse transcription.
  • a constitutively expressed gene glyceraldehyde-3 -phosphate dehydrogenase
  • Intron-spanning primers were devised to amplify a 263 base pair product of REG cDNA (Accession number Genbank/EMBL J05412) (REG upper dAACATGAATTCGGGCAACC, positions 2708....2726, exon 4; REG lower dGGCACATCCTTCCATTTCCT, positions 3880....3862, exon 6).
  • Primers (ImM) and template (1 microlitre of RT reaction product) in a final volume of 10 ⁇ l were overlaid with mineral oil and heated to 95°C for 'hot start' PCR.
  • reaction was initiated by the addition of 10 ⁇ l of PCR reaction mix, to give Taq DNA polymerase (1U), dNTPs (0.2mM each, Pharmacia) IX Taq buffer (Promega) and MgCl 2 (2mM). Reactions proceeded in a thermal cycler for 40 cycles (denaturation 60s 95°C, annealing 60s 55°C, extension 60s 72°C). PCR products were electrophoresed on 2% agarose gels containing ethidium bromide and visualised by ultraviolet transillumination. REG positivity was defined as the presence of a 263bp band.
  • the primary outcome parameter in this study was overall survival, as measured from the date of surgery to the time of the last follow-up visit or death. Data on survival were censored if the patient was still alive at the time of the last follow-up visit or had died from causes unrelated to colorectal cancer.
  • the statistical software package SPSS 6.0 was used. Actuarial survival curves were constructed according to the life- tables method and differences in survival were tested for statistical significance with the log-rank statistic. The risk of death in patients with Swrv vm-positive tumours was compared with that in patients with Swrv/vm-negative tumours using the Cox proportional hazards regression model.

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  • General Engineering & Computer Science (AREA)
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Abstract

L'invention concerne un système d'analyse permettant d'identifier l'existence d'un ou de plusieurs produits des gènes REG et Survivine combinés, de manière à déterminer la tendance au développement cancéreux d'un tissu ou la nature agressive d'un cancer existant dans le but de déterminer un pronostic et/ou une thérapie. L'invention concerne également un procédé permettant de dépister, chez des individus, l'existence d'un ou de plusieurs produits des gènes REG et Survivine combinés, de manière à déterminer si le patient doit être inclus dans une étude clinique ou en être exclu.
PCT/GB1999/001877 1998-07-01 1999-06-24 Marqueur combine du cancer WO2000001847A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45177/99A AU4517799A (en) 1998-07-01 1999-06-24 Combined cancer marker

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9814213.6A GB9814213D0 (en) 1998-07-01 1998-07-01 Survivin and REG gene expression as prognostic marker
GB9814213.6 1998-07-01

Publications (1)

Publication Number Publication Date
WO2000001847A1 true WO2000001847A1 (fr) 2000-01-13

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PCT/GB1999/001877 WO2000001847A1 (fr) 1998-07-01 1999-06-24 Marqueur combine du cancer

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AU (1) AU4517799A (fr)
GB (1) GB9814213D0 (fr)
WO (1) WO2000001847A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000561A1 (fr) * 1996-06-28 1998-01-08 Zeneca Limited Expression du gene reg dans un tissu cancereux

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000561A1 (fr) * 1996-06-28 1998-01-08 Zeneca Limited Expression du gene reg dans un tissu cancereux

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LU F.J. ET AL.,: "Serum immunosuppressive acidic protein levels in blackfoot disease patients and cancer patients", J. FORMOSAN MEDICAL ASSOCIATION, vol. 89, no. 4, - 1990, pages 255 - 258, XP002117909 *
SARELA A.I. ET AL.,: "Expression of a novel anti-apoptosis gene, survivin, predicts death due to recurrent colorectal carcinoma", GASTROENTEROLOGY, vol. 116, no. 4, - April 1999 (1999-04-01), pages a496, XP002117905 *
SARELA A.I. ET AL.,: "Survivin, a novel inhibitor of apoptosis, and prognosis in colorectal cancer", BRITISH JOURNAL OF SURGERY, vol. 85, no. 11, - November 1998 (1998-11-01), pages 1566, XP002117904 *
TOBI M. ET AL.,: "Combination of telomerase, ADNAB-9 and reg in the diagnosis of colorectal cancer", GASTROENTEROLOGY, vol. 112, no. 4, - April 1997 (1997-04-01), pages supp - A669, XP002117903 *

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Publication number Publication date
AU4517799A (en) 2000-01-24
GB9814213D0 (en) 1998-09-02

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