WO2006137751A2 - Procedes, utilisations et compositions destines a la detection d'une predisposition accrue ou reduite a divers cancers par identification de genotypes specifiques du gene cyp1b1 - Google Patents

Procedes, utilisations et compositions destines a la detection d'une predisposition accrue ou reduite a divers cancers par identification de genotypes specifiques du gene cyp1b1 Download PDF

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Publication number
WO2006137751A2
WO2006137751A2 PCT/PL2006/000040 PL2006000040W WO2006137751A2 WO 2006137751 A2 WO2006137751 A2 WO 2006137751A2 PL 2006000040 W PL2006000040 W PL 2006000040W WO 2006137751 A2 WO2006137751 A2 WO 2006137751A2
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WO
WIPO (PCT)
Prior art keywords
cyplbl
indicative
predisposition
cancers
cancer
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PCT/PL2006/000040
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English (en)
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WO2006137751A3 (fr
Inventor
Joanna Matyjasik
Jan Lubinski
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Pomeranian Academy Of Medicine
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Publication date
Priority claimed from PL375857A external-priority patent/PL214855B1/pl
Application filed by Pomeranian Academy Of Medicine filed Critical Pomeranian Academy Of Medicine
Priority to EP06769504A priority Critical patent/EP1922417A2/fr
Priority to RU2009127735/10A priority patent/RU2470998C2/ru
Priority to PCT/PL2006/000062 priority patent/WO2007148997A1/fr
Priority to PL06784044T priority patent/PL2134876T3/pl
Priority to EP06784044.7A priority patent/EP2134876B1/fr
Publication of WO2006137751A2 publication Critical patent/WO2006137751A2/fr
Publication of WO2006137751A3 publication Critical patent/WO2006137751A3/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
    • C12Q2600/172—Haplotypes

Definitions

  • Patent application US 20040002071 contains the mode of assessment of breast cancer risk by examination of at least two genes.
  • alleles increasing probability of cancer there are two CYPlBl alleles containing G or C at nucleotide position 1294 (Gene Bank accession No U 56438) which corresponds to codon 432.
  • haplotypes determined using two additional polymorphisms resulting in amino acid replacement - R48G and L432V.
  • haplotypes created using CYPlBl polymorphic SNPs and predisposition to cancers Positive association (cancer risk increased or decreased ) have been reported only by Chang et al. who indicated that haplotype G-G-C- 48 G 119 can be associated with increased risk of prostate cancer and haplotypes T-A-T-G 48 -T 119 and G 48 - T 119 -C 432 -A 453 are associated with decreased risk of prostate cancer [2].
  • This invention is aimed to provide modes and compositions which can be useful in detection of increased/decreased inherited predisposition to cancers of various sites.
  • the subject of invention is the mode of detection of genetic predisposition to cancers of various sites characterized by analysis of biological material obtained from the patient in search for homozygous 355T/T or combined genotypes based on C142G, G355T and C4326G SNPs within CYPlBl gene; the presence of any of examined variants (presented in Table A and B) in sample from patient is indicating the significantly increased/decreased predisposition to cancers of the following sites: breast, colon, kidney, larynx, lung, pancreas, prostate and, with high probability, thyroid and ovarian.
  • Table A List of CYPlBl variants associated with increased risk of cancers
  • Table B List of CYPlBl variants associated with decreased risk of cancers
  • germline change within CYPlBl gene is understood as inherited CYPlBl homozygous 355T/T or other variant (presented in Table A and B) causing production of CYPlBl protein with activity altered significantly and/or production of protein with altered sequence and potentially altered function, what is related with significantly increased/decreased risk of cancer.
  • the A119S 355T/T and other (presented in Table A and B) variant alterations are germline changes causing production of improper variants of CYPlBl protein [12,19].
  • 355 T/T homozygotes have protein with serine in 119 codon in both of alleles
  • 142 C/C homozygotes have protein with arginine in 48 codon in both of alleles
  • 4326 C/C homozygous have protein with leucine in codon 432 in both of alleles.
  • This invention refers to the increased/decreased risk of cancers of various sites in patients with T/T genotype at 355 or other variants (presented in Table A and B) of CYPlBl gene.
  • the next subject of invention is also the composition for detection of CYPlBl ge ⁇ nline changes allowing identification of person with significantly increased/decreased genetic predisposition to cancers of at least one of the following sites: breast, colon, kidney, larynx, lung, pancreas, prostate and also, most probably, thyroid and ovarian provided 355 T/T or other (presented in Table A and B) variants or changes with analogous features are studied.
  • the DNA, RNA and proteins can be used as material for diagnostic analyses.
  • diagnostic purposes it is appropriate to use also altered forms of CYPlBl DNA/RNA as well as proteins coded by corresponding alleles with alterations.
  • the next subject of invention is thus the use of polypeptide coded by the CYPlBl allele containg germline variants A119S or other (presented in Table A and B) alterations in linkage disequilibrium with above variants or changes with analogous features for detection of significantly increased/decreased genetic predisposition to cancers of at least one of the following sites: breast, colon, kidney, larynx, lung, pancreas, prostate and, with high probability, thyroid and ovarian .
  • polypeptide coded by CYPlBl allele with germline alteration is detected by antibodies or other substances specific for this polypeptide or its fragment.
  • Position of change is not determined by numbers of consecutive nucleotides or aminoacids. According to invention position of a given nucleotide or aminoacid can be marked with different numbers but has to possess the same properties.
  • Antibodies can be obtained, for example, by a method described by Kohler and Milstein, Nature 256 (1975)7 495, and in Meth. Enzymol. 73 (1981)9 3.
  • Antibodies can be monoclonal, polyclonal or fragments of the antibodies (such as Fab, Fv or scFv) can be used. They can be obtained by methods described by Harlow and Lane “Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988.
  • the next subject of invention is composition for detection of significantly increased/decreased genetic predisposition to tumors using techniques based on PCR and characterized by the use of at least two different primers allowing amplification of region containing germline change CYPlBl A119S or other variant (presented in Table A and B) or alterations in linkage disequilibrium with these variants or with analogous properties what allows detection of predisposition to cancers of the following sites: breast, colon, kidney, larynx, lung, pancreas, prostate and, probably, thyroid and ovarian .
  • the next subject of invention is application of polynucleotide containing on position corresponding to position 355 or 142 or 4326 of exon 2/3 of human gene CYPlBl the change 355 G>T or 142 G>C or 4326A>G or distinct change with analogous properties or other polynucleotide coding CYPlBl protein variant containing A119S or R48G or L432V substitution (or other with analogous properties) or polypeptide coded by above polynucleotides or antibodies specific for above polypeptides, for preparation of diagnostic composition allowing detection of significantly increased/decreased predisposition to cancers in person with CYPlBl 355 alterations coding A119S substitution or 142 alterations coding R48G substitution or 432 alterations coding L432V substitution change with analogous properties. Above predisposition is associated with increased/decreased risk of cancers of the following sites: breast, colon, kidney, larynx, lung, pancreas, prostate and, probably, thyroid
  • polynucleotide is a polynucleotide obtained using diagnostic composition according to invention.
  • examples of above polypeptide are CYPlBl polypeptide variants coded by these polynucleotides and corresponding to changes presented in Table A and B.
  • corresponding applied in this description means, that position is not determined by numbers of consecutive nucleotides or aminoacid. According to invention, position of particular nucleotide or aminoacid which can be deleted or substituted, may be distinct than in wild type gene or polypeptide. Thus, “corresponding" position according to invention means that nucleotides or aminoacid may be described using different numbers, but still have the same properties. Such nucleotides or aminoacids which can be substituted or deleted are also covered by definition of "corresponding" position.
  • the next subject of invention is the mode of identification of genetic marker associated with significantly increased/ decreased risk of malignancy development based upon evaluation of biological samples (DNA, RNA or protein) from patients affected by malignancy for the presence of germline 355T/T or other (presented in Table A and B) variants of CYPlBl or other alterations in linkage disequilibrium with these variant changes.
  • the incidence is then compared to frequency of occurrence of a given variant in general population.
  • the variant with significant overrepresentation/underrepresentation among patients with a given malignancy is considered as a genetic marker associated with significantly increased/decreased risk of malignancy development. It is valuable if the numbers of examined patients are large enough and results are considered statistically significant whenp ⁇ 0.05.
  • the next subject of invention is the mode of identification of genetic marker associated with significantly increased/ decreased risk of malignancy based on analyses of molecular data in all possible combination of genotypes. Such data are much more accurate in giving higher or lower cancer risk and diagnostically more valuable than those achieved by widely applied haplotyping based on statistical programmes.
  • 5 ml peripheral blood was obtained from patients and mixed with 100 ⁇ l IM EDTA, then was centrifuged in 50 ml polypropylene tubes by 10 minutes at 300Og in 4 0 C. Serum in upper faze was removed, and pellet containing cells was mixed with 45 ml buffer 2X (0,1M NH 4 Cl , 0,25M KHCO3, ImM EDTA) and was left for 15 minutes in 4 0 C. Then mixture was centrifuged at 300Og for 10 minutes in 4 0 C. Supernatant was removed after centrifugation. The remaining pellet with leukocytes was suspended in 2X buffer and centrifuged 10 minutes at 3000g in 4 0 C.
  • DNA was purified using phenol/chloroform.
  • digestion products was mixed with 3ml phenol buffered 0,5M Tris HCl (pH 8,4), and then 3ml chloroform and isoamyl alcohol mixture (mixed in proportion 1:25 vol/vol).
  • Mixture was agitated for about 1 minute and centrifuged 10 minutes at 8000g in 2O 0 C. After centrifugation upper faze was replaced to new tube, and mixed with equal volume of chloroform and thereafter centrifuged 10 minutes at 800Og.
  • Above described purification with chloroform was repeated 3-times until protein ring in interfaze had disappeared.
  • the purified water faze containing DNA was mixed with 5M NaCl in proportion 10:1 (vol/vol) and 96% ethanol in the proportion of water faze with NaCl to ethanol 1:10 (vol/vol). Mixture was left overnight in 2O 0 C.
  • the resultant DNA pellet was placed in a new tube and purified with 70% ethanol, centrifuged at 3000g for 5 minutes, and ethanol was poured out. Then purified DNA pellet was dried in open tube for 30 minutes at 37 0 C. DNA resuspended in 400 ⁇ l TE buffer (25mM Tris HCl, ImM EDTA; pH 8.4) was stored in 4 0 C until use.
  • the 355T/T variant alteration was identified by RFLP-PCR using Earn 11051 and Pdil restriction enzyme (Fermentas). PCR was performed with primers e.g.CYP119F (CTCGTTCGCTCGCCTGGCGC) and e.g. CYPl 19R (GAAGTTGCGCATCATGCTGT).
  • CYP119F CCGTTCGCTCGCCTGGCGC
  • CYPl 19R GAGTTGCGCATCATGCTGT
  • PCR reactions was carried out in PTC - 200 Peltier DNA ThermalCycler (MJ Research) in volume of 25 ⁇ l included: 1 ⁇ l (50ng) genomic DNA, 4 pmol each primer set, 2.5 ⁇ l PCR Buffer 2(Expand Long Template PCR System Roche - 22,5mM MgCl 2 ), 200 ⁇ M each dATP, dCTP, dGTP i dTTP and 1 U Taq DNA polymerase. In each reaction negative control (control without DNA) was used.
  • PCR conditions a) Initial denaturation - 95 0 C 15 minutes b) 15 cycles , each of: denaturation - 95 0 C 30 s primer annealing - 62-54,5 0 C 30s
  • Digestion was performed overnight at 37 0 C in volume of 24 ⁇ l containing: 12 ⁇ l PCR product, 10 x Buffer Tango (Fermentas) and 2U Earn 11051 enzyme (Fermentas). Then, 15 ⁇ l of digestion product was mixed with 10 ⁇ l loading buffer and was electrophoresed in agarose gel (3% agarose gel (SeaKem FMC), IX bufor TBE, 25 ⁇ g/ml ethidium bromide) at 6V/cm for 30 minutes. Separated PCR products were visualized in UV light.
  • agarose gel 3% agarose gel (SeaKem FMC), IX bufor TBE, 25 ⁇ g/ml ethidium bromide
  • PCR product 250bp was digested on two fragments: 136bp and 114bp in cases which containing nucleotide T in 355 nucleotide site of CYPlBl gene. All cases with alterations are verified by using Pdil enzyme restriction (Fermentas). Restriction mixture in volume 18 ⁇ l containing: 4 ⁇ l PCR product, 1O x Buffer Tango (Fermentas) and 2U Pdil enzyme (Fermentas). Then, 15 ⁇ l digestion product was electophoresed in the same conditions.
  • PCR product (250bp) was digested on two fragments: 138bp and 112bp in cases which containing nucleotide G in 355 nucleotide site of CYPlBl gene.
  • randomly selected cases with G/G, T/T and G/T variants were sequenced in order to confirm the presence of the A119S change. Sequencing was prepared by using conventional methods. Purification of PCR product i
  • Sequencing product were placed on Microcon - 100 (Amicon) column which fit on 0,5 ml Eppendorf tube. 400 ⁇ l distillated water was added, then centrifuged for 15 minutes at 1850g in 25 0 C. The columns were 4 times washed with 400 ⁇ l of distillated water. After the last washing step, the columns were turned up side down and placed on a new Eppendorf tube. By centrifugation for 3 minutes at 900Og we obtain 5 ⁇ l purified PCR product which were 4 times diluted with distillated water.
  • PCR reactions was carried out in PTC - 200 Peltier DNA ThermalCycler (MJ Research) in volume of 25 ⁇ l included: 1 ⁇ l (50ng) genomic DNA, 4 pmol each primer set, 2.5 ⁇ l PCR Buffer
  • Sequencing product were placed on Microcon - 100 (Amicon) column which fit on 0,5 ml Eppendorf tube. 400 ⁇ l distillated water was added, then centrifuged for 15 minutes at 185Og in 25 0 C. The columns were 4 times washed with 400 ⁇ l of distillated water. After the last washing step, the columns were turned up side down and placed on a new Eppendorf tube. By centrifugation for 3 minutes at 9000g we obtain 5 ⁇ l purified PCR product which were 4 times diluted with distillated water.
  • the variants of L432V alteration was identified by RFLP-PCR using OHI restriction enzyme (Fermentas). PCR was performed with primers e.g. CYP1294F (ATGCGCTTCTCCAGCTTTGT) and e.g. CYP1294R (TATGGAGCACACCTCACCTG).
  • PCR reactions was carried out in PTC - 200 Peltier DNA ThermalCycler (MJ Research) in volume of 25 ⁇ l included: 1 ⁇ l (50ng) genomic DNA, 4 pmol each primer set, 2.5 ⁇ l PCR Buffer 2(Expand Long Template PCR System Roche - 22,5mM MgCl 2 ), 200 ⁇ M each dATP, dCTP, dGTP i dTTP and 1 U Taq DNA polymerase. In each reaction negative control (control without DNA) was used.
  • PCR conditions c) Initial denaturation - 95 0 C 15 minutes b) 10 cycles , each of: denaturation - 95 0 C 30 s primer annealing - 62-57 0 C 30s
  • PCR product 15 ⁇ l was mixed with 10 ⁇ l loading buffer and was electrophoresed in agarose gel (3% agarose gel (SeaKem FMC), IX bufor TBE, 25 ⁇ g/ml ethidium bromide) at 6V/cm for 30 minutes. Separated PCR products were visualized in UV light. PCR product (623bp) was digested on two fragments: 132bp and 491bp in cases which containing nucleotide C in 4329 nucleotide site of CYPlBl gene, hi addition, randomly selected cases with G/G, C/C and C/G variants were sequenced in order to confirm the presence of the L432V change. Sequencing was prepared by using conventional methods. Purification of PCR product
  • Sequencing product were placed on Microcon - 100 (Amicon) column which fit on 0,5 ml Eppendorf tube. 400 ⁇ l distillated water was added, then centrifuged for 15 minutes at 1850g in 25 0 C. The columns were 4 times washed with 400 ⁇ l of distillated water. After the last washing step, the columns were turned up side down and placed on a new Eppendorf tube. By centrifugation for 3 minutes at 900Og we obtain 5 ⁇ l purified PCR product which were 4 times diluted with distillated water. Results
  • Prostate GG 48 CC 432 GG 48 TT 119 15.4 TT 119 CC 432 The herein invention, is showing for the first time that constitutional alterations of CYPlBl 355 T/T or other variants (presented in Table A and B) are the markers of significantly increased or decreased susceptibility to cancers of various sites, especially to tumor types described above. Suggested DNA testing is allowing identification of groups of individuals who should be covered by special programs of surveillance and prevention.
  • IBl (CYPlBl) polymorphism with steroid receptor status in breast cancer. Cancer Res., 58,

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Abstract

La présente invention concerne des procédés, des utilisations et des compositions utiles dans le diagnostic des prédispositions aux cancers humains de divers sites, les variants constitutionnels d'altérations dans le gène CYPlBl étant analysés dans une matière biologique du patient examiné. Ce mode peut être appliqué pour l'examen de personnes d'origine polonaise et probablement aussi d'autres groupes ethniques.
PCT/PL2006/000040 2005-06-23 2006-06-22 Procedes, utilisations et compositions destines a la detection d'une predisposition accrue ou reduite a divers cancers par identification de genotypes specifiques du gene cyp1b1 WO2006137751A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP06769504A EP1922417A2 (fr) 2005-06-23 2006-06-22 Procedes, utilisations et compositions destines a la detection d'une predisposition accrue ou reduite a divers cancers par identification de genotypes specifiques du gene cyp1b1
RU2009127735/10A RU2470998C2 (ru) 2006-06-22 2006-09-06 Определение предрасположенности к раку путем идентификации генотипических комбинаций специфичных вариантов генов cyp1b1, brca2 и снек2
PCT/PL2006/000062 WO2007148997A1 (fr) 2006-06-22 2006-09-06 Détermination de la prédisposition au cancer par l'identification de combinaisons génotypiques de variants spécifiques des gènes cyp1b1, brca2 et chek2
PL06784044T PL2134876T3 (pl) 2006-06-22 2006-09-06 Określanie predyspozycji do raka piersi poprzez identyfikację kombinacji genotypu specyficznych wariantów genów CYP1B1, BRCA2 oraz CHEK2
EP06784044.7A EP2134876B1 (fr) 2006-06-22 2006-09-06 DÉTERMINATION DE LA PRÉDISPOSITION AU CANCER Du SEIN PAR L'IDENTIFICATION DE COMBINAISONS GÉNOTYPIQUES DE VARIANTS SPÉCIFIQUES DES GÈNES CYP1B1, BRCA2 ET CHEK2

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US69314905P 2005-06-23 2005-06-23
PL375857A PL214855B1 (pl) 2005-06-23 2005-06-23 Sposób wykrywania genetycznie uwarunkowanej predyspozycji do nowotworów różnych narządów poprzez identyfikację wariantu genu CYP1B1 oraz zastosowania obejmujące taką zmianę
US60/693,149 2005-06-23
PLP375857 2005-06-23

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WO2006137751A2 true WO2006137751A2 (fr) 2006-12-28
WO2006137751A3 WO2006137751A3 (fr) 2008-04-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002004683A2 (fr) * 2000-07-11 2002-01-17 Vanderbilt University Methode de detection d'une sensibilite accrue au cancer du sein
WO2002030951A2 (fr) * 2000-10-13 2002-04-18 Genaissance Pharmaceuticals, Inc. Haplotypes du gene cyp1b1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002004683A2 (fr) * 2000-07-11 2002-01-17 Vanderbilt University Methode de detection d'une sensibilite accrue au cancer du sein
WO2002030951A2 (fr) * 2000-10-13 2002-04-18 Genaissance Pharmaceuticals, Inc. Haplotypes du gene cyp1b1

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SASAKI M. ET AL.,: "polymorphisms of the cyp1b1 gene as risk factors for human renal cell cancer" CLINICAL CANCER RESEARCH, vol. 10, 15 March 2004 (2004-03-15), pages 2015-2019, XP002412158 *
WANQING WEN ET AL.,: "cytochrome p450 1b1 and catechol-o-methyltransferase genetic polymorphisms and breast cancer risk in chinese women: results from shanghai breast cancer study and a meta-analysis" CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION, vol. 14, no. 2, February 2005 (2005-02), pages 329-335, XP002412157 *
WATANABE J. ET AL.,: "association of cyp1b1 genetic polymorphism with incidence to breast and lung cancer" PHARMACOGENETICS, vol. 10, 2000, pages 25-33, XP009076429 cited in the application *

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