WO2009056862A2 - Dépistage de la susceptibilité au cancer de la prostate - Google Patents

Dépistage de la susceptibilité au cancer de la prostate Download PDF

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WO2009056862A2
WO2009056862A2 PCT/GB2008/003711 GB2008003711W WO2009056862A2 WO 2009056862 A2 WO2009056862 A2 WO 2009056862A2 GB 2008003711 W GB2008003711 W GB 2008003711W WO 2009056862 A2 WO2009056862 A2 WO 2009056862A2
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chromosome
human genome
allele
genome build
positions
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WO2009056862A3 (fr
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Rosalind Eeles
Douglas Easton
David Austin Neal
Graham Giles
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Cancer Research Technology Ltd
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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
    • C12Q2600/112—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
    • C12Q2600/136—Screening for pharmacological compounds

Definitions

  • the invention relates to oncology and methods of screening for prostate cancer susceptibility.
  • the field of the invention therefore concerns markers of predictive or clinical value in prostate cancer diagnosis.
  • the invention also includes apparatus and systems used in the methods of screening.
  • PrCa Prostate cancer
  • KLK2 and KLKS are 2 of 15 kallikrein subfamily members located in a cluster on chromosome 19.
  • Prostate specific antigen PSA is a serine protease which liquefies semen and as a serum marker is used in screening and disease monitoring; there is also evidence that hK2 may also be useful for screening and prognosis [16, 17].
  • PSA Prostate specific antigen
  • hK2 may also be useful for screening and prognosis
  • Many kallikreins are implicated in carcinogenesis [18].
  • Multiple SNPs in the promoter region have been associated with PSA levels [19] and some have been suggested to be associated with PrCa risk [20].
  • SNPs single nucleotide polymorphisms
  • the inventors have discovered that certain SNPs are associated with increased risk of prostate cancer.
  • the invention provides a method of determining susceptibility of an individual to prostate cancer comprising obtaining a sample of genetic material from the individual and determining the presence of at least one minor allele selected from one or more of the following major/minor alleles: (i) C/T on chromosome 10 between human genome Build 36 positions
  • the method of the invention may also be used in conjunction with one or more known methods of screening for prostate cancer susceptibility.
  • the method may further comprise determining the presence of one or more major/minor alleles of 8q24: a. G/T on chromosome 8 between human genome Build 36 positions
  • A/C on chromosome 8 between human genome Build 36 positions 128391369 - 128616342, preferably 128587736.
  • the method may further comprise determining the presence of one or major/minor alleles of 17ql2; preferably wherein the allele is associated with TCF2; more preferably wherein the allele is C/T on chromosome 17 between human genome Build 36 positions 33119634 - 33207727; even more preferably at position 33175269.
  • the method may further comprise determining the presence of one or more major/minor alleles of 17q24, preferably T/G on chromosome 17 between human genome Build 36 positions 66616213 - 66754527; preferably position 66620348.
  • any combination of one or more alleles may be selected.
  • Alleles of (iii) and/or (i) may be associated with the microseminoprotein beta gene (MSMB); preferably the alleles lie within MSMB.
  • MSMB microseminoprotein beta gene
  • Allele (iii) which is A/G on chromosome 10 may be as shown in SEQ ID NO: 4, preferably at human genome Build 36 position 51202627.
  • allele (i), which lies upstream of the transcription start site of MSMB, preferably 2 base pairs upstream thereof; and/or the allele of (i) may be associated with removal of multiple predicted binding sites for transcription and splicing factors; and/or the allele of (i) may be associated with androgen and/or estrogen receptor binding sites, preferably such sites are less than 50bp upstream of the allele (i).
  • the allele of (i) is CfY on chromosome 10 as shown in SEQ ID NO: 5; preferably at human genome Build 36 position 51219502.
  • Allele (iv) may be associated with Kallikrein-related peptidase 2 (KLK2) and/or KLK3 (PSA), preferably the allele is located between KLK2 and KLK3, preferably located 3 ' of KLK3.
  • KLK2 Kallikrein-related peptidase 2
  • PSA KLK3
  • allele of (iv) is G/A on chromosome 19 as shown in SEQ ID NO: 10, preferably at human genome Build 36 position 56056435.
  • Allele (v) may be associated with LMTK2 encoding a neuronal kinase, cyclin- dependent kinase 5 (cdk5)/p3 -regulated kinase (cprk) and Brain-Enriched Kinase (BREK), preferably wherein allele (v) lies in LMTK2, more preferably the allele lies in an intron of LMTK2, more preferably intron 9 of LMTK2.
  • allele (v) may be associated with basic helix-loop-helix BHLHB8, preferably wherein the allele is located upstream of BHLHB8.
  • the allele of (v) is T/C on chromosome 7 as shown in SEQ ID NO: 3, preferably at human genome Build 36 position 97460978.
  • Allele (vi) may be associated with solute carrier family 22 (organic cation transporter (OCT)) genes and/or LPAL2 and/or LPA genes, preferably wherein the allele lies in SLC22A2 and/or SLC22A3, more preferably wherein the allele lies in an intron of SLC22A3, even more preferably intron 5 of SLC22A3.
  • OCT organic cation transporter
  • the allele of (vi) is C/T on chromosome 6 as shown in SEQ ID NO: 2, preferably at human genome Build 36 position 160804075.
  • Allele (xi) may be associated with one or more of: a. nudix (nucleoside diphosphate linked moiety X)-type motif 10 (NUDTlO); b. nudix (nucleoside diphosphate linked moiety X)-type motif 11 (NUDTl 1); c. GTP binding protein (GSPT2); d. MAGED l; e. MAGED 4; f. MAGED 4B; g- CTD-2267G17.3; h. XAGE 2; i. XAGElC; j- XAGE ID; k. XAGE 3;
  • S. TMEM 29B preferably the allele is located between NUDTlO and NUDTl 1, more preferably about 2kb upstream of NUDTI l.
  • the allele (xi) is T/C on chromosome X as shown in SEQ ID NO: 11, preferably at human genome Build 36 position 51074708.
  • Allele (ii) may be associated with a gene poor region, preferably with chromatin modifying protein 2B (CHMP2B) and/or pituitary-specific transcription factor (POUlFl (PITl)), preferably upstream of CHMP2B, more preferably 170 kb upstream of CHMP2B.
  • CHMP2B chromatin modifying protein 2B
  • POUlFl pituitary-specific transcription factor
  • the allele of (ii) is C/T on chromosome 3 is as shown in SEQ ID NO: 1, preferably at human genome Build 36 position 87193364.
  • Allele (vii) may lie in an LD block of 70kb on chromosome 11.
  • the allele of (vii) is G/T on chromosome 11 as shown in SEQ ID NO: 6, preferably at human genome Build 36 position 68751073.
  • Allele (viii) which is G/A on chromosome 12 may be as shown in SEQ ID NO: 7, preferably at human genome Build 36 position 51560171.
  • Allele (ix) which is A/G on chromosome 19 may be as shown in SEQ ID NO: 8, preferably at human genome Build 36 position 56027755.
  • Allele (x) which is A/G on chromosome 19 may be as shown in SEQ ID NO: 9, preferably at human genome Build 36 position 56040902.
  • the method may further comprise obtaining a fluid sample from the individual and determining the amount of prostate cancer marker substance therein.
  • the marker substance may be specific for the presence of prostate cancer in an individual, e.g. prostate specific antigen (PSA).
  • PSA prostate specific antigen
  • samples may be obtained from patients by other methods well known in the art, including but not limited to, samples of blood, serum, urine, ascites and intraperitoneal fluids.
  • Blood samples may be taken via venepuncture, (e.g. by vacuum collection tube or syringe,) catheter, cannula, or by finger prick or heel prick as appropriate to the needs of the patient and the amount of blood required.
  • a blood sample Once a blood sample has been taken it may be treated prior to analysis (e.g. with sodium citrate, EDTA, ethanol or Heparin) for the purposes of preservation or in order to maximise the accuracy and/or reliability of the signal obtained by analysis of the sample.
  • Methods of processing may be used to separate a blood sample into fractions each of which may be tested independently.
  • a blood serum sample is produced by allowing a whole-blood sample to clot on contact with air where the clotted fraction is removed by centrifugation to leave the serum as the supernatant.
  • Urine samples are preferably collected by urination or catheterisation.
  • the cells and/or liquid collected in a sample taken from a patient may be processed immediately or preserved in a suitable storage medium for later processing.
  • a suitable storage medium for later processing.
  • the sample may be treated for the purposes of preservation or for maximising the accuracy and/or reliability of the signal obtained by analysis of the sample.
  • Methods of processing e.g. centrifugation and/or filtration
  • the method may be used to test individuals of any age and for any combination of alleles. However the method may include testing for the allele (iv) and/or (xi) optionally in instances when the individual may be less than 55 years old; optionally less than 50, 45, 40, 35, 25, 20 or 15 years old.
  • the individual is a male.
  • Females can also be screened for presence or absence of the risk alleles that may be passed down through the germ line.
  • quantity of each allele in a sample may be measured using a quantitative polymerase chain reaction (qPCR) method.
  • qPCR quantitative polymerase chain reaction
  • the amount of each allele is compared to an amount of another marker, including those alleles being a part of the invention, within the sample and/or with reference to samples containing a known amount of the marker.
  • the invention also provides a device for detection of risk of prostate cancer in an individual, comprising at least one surface or volume for receiving a sample, and a nucleic acid molecule hybridisable to at least one target nucleic acid in the sample, the target nucleic acid comprising one of the following major/minor alleles:
  • nucleic acid molecule may be hybridisable to the target under stringent conditions.
  • 'stringent conditions' is a term well known in the art and refers to conditions wherein only DNA molecules with a defined degree of sequence similarity can hybridise efficiently to complementary DNA.
  • the 'stringent conditions' are normally user defined by choices in, for example, temperature, divalent cation concentration (usually Mg 2+ or Mn 2+ ) and pH. In this way, by varying the conditions, the user can limit efficient hybridisation to only that subset of DNA molecules that hybridise most accurately.
  • a DNA microarray also known as gene or genome chip, DNA chip, or gene array
  • Qualitative or quantitative measurements with DNA microarrays utilize the selective nature of DNA-DNA or DNA-RNA hybridization under high-stringency conditions.
  • Fluorophore-based detection may be used to determine the degree of hybridisation from which a quantitative measurement may be calculated.
  • a tag may be present, such that on hybridization of the nucleic acid molecule to a target nucleic acid molecule the tag may be retained in association with the target nucleic acid.
  • the tag may be selected from one or more of the following: fluorescent substance, a luminescent substance, a protein, an antibody or fragment thereof, a radiolabel, a metal particle, a nanomaterial, a nanoparticle.
  • Fluorescent substances may be created by including a fluorophore (e.g. FITC, rhodamine, Texas Red) either attached or within the substance that emits a detectable signal when excited by a suitable source of energy. Normally this is light of a specific wavelength and is often a LASER.
  • a fluorophore e.g. FITC, rhodamine, Texas Red
  • Luminescent substances produce light. Normally this is achieved by conjugating an enzyme that catalyses a light producing chemical reaction in the presence of a suitable substrate.
  • enzymes include luciferase and alkaline phosphatase.
  • Particles of colloidal gold or tungsten may be attached to molecules and used as labels for these molecules.
  • the metal allows the detection of the molecule attached by detecting the mass, electron density or other property of the metal.
  • a nanoparticle is a microscopic particle with at least one dimension less than 100 run.
  • nanoparticles have been created and are known to the art, e.g. nanospheres, nanorods, and nanocups have been created and collectively go by the name of nanomaterials.
  • metal, dielectric, and semiconductor nanoparticles have been formed, as well as hybrid structures (e.g., core-shell nanoparticles).
  • Nanoparticles made of semiconducting material may also be called quantum dots if they are small enough (typically sub 10 nm) that quantization of electronic energy levels occurs. Such nanoscale particles are known in the art and used in biomedical applications e.g. as labels for specific molecules or drug carriers.
  • Radioisotopic labelling is a technique that uses radioactive isotopes for tracking the passage of a sample of substance through a system.
  • the substance is "labelled" by including radioactive isotopes in its chemical composition. When these 'radiolabels' decay, their presence can be determined by detecting the radiation they emit. Examples of this include the incorporation of P or P into DNA probes or labelling of proteins with 125 I and/or 35 S.
  • the nucleic acid molecule may be linked to a surface, optionally wherein the nucleic acid molecule forms part of an array of a multiplicity of species of nucleic acid molecule.
  • the number and density of this multiplicity of species of nucleic acid molecule may be varied over a wide range and in alternative embodiments of the invention there are fewer than 100,000 species of nucleic acid molecule; preferably fewer than 50,000, more preferably fewer than 10,000, even more preferably fewer than 1000, 500, 400, 300, 200, 100, 75, 50, 25.
  • Another advantage of the invention may be the inclusion of indicia or label identifying the location of the nucleic acid molecule on a surface or within an array.
  • An embodiment of the invention may also comprise instructions directing a user to obtain a sample of genetic material and expose this to the device for the purpose of determining prostate cancer risk in the individual from whom the sample was taken.
  • a device as described herein may comprise a detector for the tag, wherein the detector generates a signal and thereby data corresponding to the presence of tag.
  • These embodiments may further comprise; a. a light source, plasmon resonance detection surface and a plasmon resonance detector; or b. a mass detector arranged for detection of change in mass on the sample receiving surface or in the sample receiving volume.
  • any of the devices and/or methods as described herein may further comprise a microprocessor programmed to receive tag data and perform operations on the data and to generate a data output, preferably wherein the operations include comparison of the tag data to reference data.
  • the invention also provides a system for determining the risk of prostate cancer in an individual from a sample of genetic material obtained from the individual, comprising any of the devices described herein and an apparatus for receiving the device, wherein the apparatus comprises a detector for the tag and wherein the detector generates a signal and thereby data corresponding to the presence of tag.
  • the invention further provides a method of screening for risk of prostate cancer in an individual comprising obtaining a sample from the individual and determining the presence and/or amount of one or more of the MSMB, LMTK2 and KLK3 gene products.
  • the invention also provides a method of screening for agents active against or preventative of prostate cancer, comprising exposing a test agent to an expression system expressing one or more of MSMB, LMTK2 and KLK3 gene products or fragments thereof, and measuring any change in the expression and/or activity of the gene product(s) or fragments thereof.
  • the gene products screened in the conduct of the invention may include mRNA, proteins and fragments thereof.
  • the mRNA level may be measured by a quantitative polymerase chain reaction (qPCR) method, preferably a qPCR method where the template is the product of a reverse transcriptase reaction (RT-qPCR.)
  • qPCR quantitative polymerase chain reaction
  • RT-qPCR reverse transcriptase reaction
  • mRNA may be extracted from the sample and reverse transcribed to produce cDNA prior to qPCR.
  • Determining the presence and/or amount of one or more of the MSMB, LMTK2 and KLK3 gene products may be measured using a nuclease protection assay, preferably the probe used is specific for MSMB and/or LMTK2 and /or KLK3.
  • the mRNA level may be measured using a DNA microarray.
  • Gene products may also be detected by means of an antibody specific for the gene product or a fragment thereof, preferably the antibody is monoclonal.
  • the antibody may be a Fab fragment wherein said Fab fragment may be selected from the group consisting of: scFv, F(ab') 2 , Fab, Fv and Fd fragments; or CDR3 regions.
  • the fragment antigen binding is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope — the antigen binding site — at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens.
  • Fc and Fab fragments can be generated.
  • the enzyme papain can be used to cleave an immunoglobulin monomer into two Fab fragments and an Fc fragment.
  • the enzyme pepsin cleaves below the hinge region, so a F(ab')2 fragment and a Fc fragment may be formed.
  • the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv), which is only half the size of the Fab fragment yet retains the original specificity of the parent immunoglobulin.
  • a complementarity determining region is a short amino acid sequence found in the variable domains of antigen receptor (e.g. immunoglobulin and T cell receptor) proteins that complements an antigen and therefore provides the receptor with its specificity for that particular antigen.
  • antigen receptor e.g. immunoglobulin and T cell receptor
  • Most of the sequence variation associated with immunoglobulins and T cell receptors are found in the CDR regions, these regions are sometimes referred to as hypervariable domains.
  • CDR3 shows the greatest variability as it is encoded by a recombination of the VJ regions.
  • FIG. 1 Figure 3 A, 3B and 3C. Table showing the summary results for 15 SNPs selected for genotyping in stage 2.
  • Figure 4A, 4B, 4C and 4D Table showing the details of 53 SNPs reaching p ⁇ 10 ⁇ 6 in stage 1.
  • Figure 7 Table showing the age-specific odds ratios in stage 2 for each SNP.
  • Figure 8A and 8B Table showing the call rates, Hardy- Weinberg tests and Homogeneity tests.
  • Figure 9 Genotype counts, by study and SNP.
  • Figure 10. Table summarising SNP position and LD plots.
  • 1,906 prostate cancer cases and 1,934 controls collected through national studies in the UK were studied; the final number analysed after exclusions (see methods) was 1854 cases and 1894 controls (figure 2).
  • PSA prostate specific antigen
  • the case series was further "enriched" by including men diagnosed aged ⁇ 60 years or with a family history of PrCa, since these cases are thought to be more likely to carry susceptibility alleles, thereby increasing the statistical power of the study.
  • stage 2 Based on the effect size seen in stage 2 (that is, ignoring the effect of enrichment of the stage 1 set), the inventors had approximately 52% power to detect the MSMB association, rising to close to 100% power based on the effect size seen stage 1. Based on the estimated relative risks in stage 2 of this study, the susceptibility loci discovered would together explain approximately 6% of the familial risk of PrCa, with MSMB being the most significant (-2% of the familial risk, comparable to the two strongest 8q loci).
  • PrCa is genetically complex.
  • the loci include plausible candidates, including a kinase gene, loci without obvious candidates and one gene desert, suggesting that diverse pathways are likely to be involved.
  • the involvement of MSMB highlights a role for its product in PrCa screening, whilst LMTK2 provides a potential therapeutic target.
  • risk counseling There is also potential for risk counseling.
  • the relative risks conferred by these loci are modest: the homozygote relative risk for rsl0993994 at MSMB was 1.61 fold (95%CI 1.40- 1.86). rs2660753 had the highest homozygote OR (2.08), but with a wide confidence interval.
  • mice for stage 1 men aged >50 years with a PSA of ⁇ 0.5ng/ml were selected. Men known to be non- white were excluded. 2,001 controls were selected to be frequency matched to the geographical distribution of the cases.
  • Stage 2 comprised PrCa cases and controls from the UK and Australia.
  • Stage 1 genotypes were generated using the Illumina Inf ⁇ nium HumanHap550 array. Only samples which called on at least 97% of SNPs at a confidence score of ⁇ .25 were used. Owing to a re-synthesis of the headset between the stages, the marker sets (versions 1 and 3) are slightly different: 534,446 SNPs were common to both sets, 14,356 markers were unique to version 1 and 20,441 markers were unique to version 3. Data on 3840 individuals (1906 cases, 1934 controls): 323 typed on version 1 and 3525 on version 3 (including 8 duplicates typed on both versions) were used.
  • SNPs re-evaluated in stage 2 were from the common set of SNPs, and for simplicity the QQ plot and summary results utilise this SNP set. SNPs were selected for evaluation in stage 2 on the basis of a significance level of p ⁇ 10 " based on a ldf trend test. SNPs from the previously reported regions of association on 8q24 and 17q were excluded. Multiple logistic regression was conducted using the set of SNPs in each of the remaining regions, to define SNPs that showed evidence of independent association at p ⁇ .05. Genotyping in stage 2 was performed by 5'nuclease assay (TaqmanTM) using the ABI Prism 7900HT sequence detection system according to the manufacturer's instructions.
  • TaqmanTM 5'nuclease assay
  • IBS identity-by-state
  • Figure 1 shows the Q-Q plot for the distribution of test statistics for comparison of genotype frequencies in cases versus controls (1 degree of freedom (df) Cochran- Armitage trend test).
  • stage 1 For each confirmed SNP, the estimated per allele odds ratios is stronger for stage 1 than stage 2. This may reflect how the inventors have restricted attention to highly significant loci (so called "winner's curse"), or it may reflect, at least in part, the enriched nature of the cases and controls in stage 1. For these reasons only the OR estimates from stage 2 are regarded as valid estimates of the relative risks in the general population.
  • the associations of the SNPs with PSA level in a sample of 1679 UK controls in stage 2 were investigated. Three of the SNPs, rs 10993994, rs7920517 and rs2735839, were strongly associated with PSA level in the same direction as the association with PrCa risk (figure 5).
  • the results were compared with the publicly available results from the Cancer Genetic Markers of Susceptibility (CGEMS) study, a genome scan of 1,117 screen detected PC cases and 1,105 controls that used the same platform (http://cgems.cancer.gov/).
  • CGEMS Cancer Genetic Markers of Susceptibility
  • the seven novel susceptibility regions contain several strong candidate genes.
  • rs 10993994 and rs7920517 lie within an LD block of -100kb on chromosome 10, containing the microseminoprotein beta gene, MSMB.
  • the most strongly associated SNP, rs 10993994, lies 2bp upstream of the transcription start site of MSMB. This SNP may be causally related to disease risk. It is noted that the risk allele of this SNP removes multiple predicted binding sites for transcription and splicing factors (http://www.genomatics.com). Putative androgen and estrogen receptor binding sites lie less than 50bp upstream of this SNP.
  • MSMB encodes for PSP94, a member of the immunoglobulin binding factor family which is synthesized by the epithelial cells of the prostate gland and secreted into seminal plasma.
  • the expression of the encoded protein has been found to be decreased in prostate cancer and loss of expression of PSP94 has been found to be associated with recurrence after radical prostatectomy [15].
  • rs2735839 lies between KLK2 (Kallikrein-related peptidase 2; hK2) and KLK3 (PSA).
  • rs27358389 lies 3' of KLK3 and shows a much stronger association with PSA levels than those previously reported, suggesting a novel functional effect.
  • rs6465657 lies in intron 9 of LMTK2 (cprk; BREK; Brain-Enriched Kinase) [21]. It encodes a neuronal kinase, cyclin-dependent kinase 5 (cdk5)/p35-regulated kinase (cprk). Cprk is expressed in a number of tissues but is enriched in brain and muscle. Somatic mutations in LMTK2 have been found in a small proportion of lung and colon cancers [22]. rs6465657 also lies upstream of basic helix-loop-helix BHLHB8 which is a transcription factor expressed at high levels in the adult seminal vesicle and during seminal gland differentiation. Mice that do not express bhlhb ⁇ have disruption of the epithelial cellular architecture [23].
  • rs9364554 lies in intron 5 of the gene SLC22A3 which is one of the solute carrier family 22 (organic cation transporter; OCT) genes.
  • OCT organic cation transporter
  • Polyspecific OCTs in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins.
  • This gene is one of three similar cation transporter genes located in a cluster on chromosome 6. Two of these, SLC22A3 and SLC22A2 are both in the LD block containing rs9364554.
  • SLC22A2 is part of the PI3 kinase and cyclic AMP-dependent protein kinase A catalytic subunit pathway [24] and is activated by a calmodulin - dependent signalling pathway [25].
  • Downstream of these genes in the LD block are genes involved in lipoprotein metabolism: LPAL2 and LPA. Polymorphisms in these genes have been reported to be associated with an increased risk of coronary artery disease [26]. Some studies have shown a protective effect of lipid lowering drugs (statins) on risk of advanced PrCa [27].
  • rs5945619 is in an LD block of approximately 2MB on Xp. It lies between NUDTlO and NUDTIl [nudix (nucleoside diphosphate linked moiety X)-type motif 11], about 2kb upstream of the latter. These genes encode isoforms of diphosphoinositol polyphosphate phosphohydrolase which determine the rate of phosphorylation in DNA repair, stress responses and apoptosis [28].
  • GSPT2 a GTP binding protein
  • MAGEDs 1, 4 B, 4 melanoma antigen genes expressed in the testes
  • CTD-2267G17.3 a GTP binding protein
  • XAGEs 2, 1C, ID, 5, 3 encoding a family of cancer/testis- associated antigens
  • SSXs 8, 7, 2, 2B a family of synovial sarcoma X breakpoint proteins which may function as transcriptional repressors
  • SPANXN5 and TMEMs 29B and 29 are also in the LD block.
  • rs2660753 is in a gene-poor region on chromosome 3. It is 170kb upstream of CHMP2B (chromatin modifying protein 2B), which encodes a component of the endosomal ESCRTIII complex; mutations in this gene have been described in frontotemporal and neurodegenerative disease [29].
  • the LD block also contains POUlFl (PITl) which is a pituitary-specific transcription factor.
  • rs7931342 lies in an LD block of 70kb on chromosome 11 that contains no recognised genes.

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Abstract

Un panneau de marqueurs de la susceptibilité au cancer de la prostate permet le dépistage pour identifier des personnes à haut risque de développer le cancer de la prostate. On peut offrir à de telles personnes un suivi et une gestion cliniques plus rapprochés pour assurer un diagnostic et une intervention au moment opportun. On a observé qu'un nombre de polymorphismes simple nucléotide (SNP) se lient à des sites/gènes qui sont susceptibles de jouer des rôles fonctionnel/causal dans le cancer de la prostate. Le SNP les plus étroitement associés (rs 10993994) est le 2bp en amont du site de début de la transcription du gène MSMB. Le gène MSMB code pour le PSP94 qui est un facteur de liaison à l'immunoglobuline qui est produit par les cellules épithéliales de la prostate et sécrété dans le fluide séminal. Il a été établi que la perte de PSP94 est associée à la récurrence tumorale chez des patients suivant une prostatectomie. La seconde association en termes d'importance est pour le SNP rs2735839 qui se situe entre les gènes de la kallikréine-2 et -3. Ces gènes ont également été liés au cancer de la prostate et proposés comme marqueurs possibles. D'autres SNP sont associés de manière significative à la susceptibilité de personnes au cancer de la prostate.
PCT/GB2008/003711 2007-11-02 2008-10-31 Dépistage de la susceptibilité au cancer de la prostate WO2009056862A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012031207A2 (fr) 2010-09-03 2012-03-08 Wake Forest University Health Sciences Procédés et compositions pour la corrélation de marqueurs génétiques au risque de cancer de la prostate
WO2012029080A1 (fr) * 2010-08-30 2012-03-08 Decode Genetics Ehf Variants de séquence associés à des taux d'antigène spécifique de la prostate
CN103060432A (zh) * 2012-10-19 2013-04-24 卫生部北京医院 一种预测前列腺癌易感性的方法和检测试剂盒
CN103060434A (zh) * 2012-10-19 2013-04-24 卫生部北京医院 一种预测前列腺癌易感性的试剂和方法
CN103432593A (zh) * 2013-08-01 2013-12-11 中山大学附属肿瘤医院 一种用于预防或治疗食管癌的药物组合物
US9534256B2 (en) 2011-01-06 2017-01-03 Wake Forest University Health Sciences Methods and compositions for correlating genetic markers with risk of aggressive prostate cancer
US10260104B2 (en) 2010-07-27 2019-04-16 Genomic Health, Inc. Method for using gene expression to determine prognosis of prostate cancer
US10703822B2 (en) 2008-06-04 2020-07-07 Modiquest B.V. Anti-inflammatory agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009814A2 (fr) * 2001-07-25 2003-02-06 Millennium Pharmaceuticals, Inc. Nouveaux genes, compositions, trousses et methodes d'identification, evaluation, prevention, et traitement du cancer de la prostate
WO2005007830A2 (fr) * 2003-07-14 2005-01-27 Mayo Foundation For Medical Education And Research Procedes et compositions pour diagnostic, stadage et pronostic du cancer de la prostate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009814A2 (fr) * 2001-07-25 2003-02-06 Millennium Pharmaceuticals, Inc. Nouveaux genes, compositions, trousses et methodes d'identification, evaluation, prevention, et traitement du cancer de la prostate
WO2005007830A2 (fr) * 2003-07-14 2005-01-27 Mayo Foundation For Medical Education And Research Procedes et compositions pour diagnostic, stadage et pronostic du cancer de la prostate

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AMUNDADOTTIR L T ET AL: "A common variant associated with prostate cancer in European and African populations" NATURE GENETICS, NATURE PUBLISHING GROUP, NEW YORK, US, vol. 38, no. 6, 7 May 2006 (2006-05-07), pages 652-658, XP002396336 ISSN: 1061-4036 *
BEKE L ET AL: "The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2" ONCOGENE, vol. 26, no. 31, July 2007 (2007-07), pages 4590-4595, XP002513955 ISSN: 0950-9232 *
BUCKLAND PAUL R ET AL: "Strong bias the location of functional promoter polymorphisms" HUMAN MUTATION, vol. 26, no. 3, September 2005 (2005-09), pages 214-223, XP002513954 ISSN: 1059-7794 *
EELES ROSALIND A ET AL: "Multiple newly identified loci associated with prostate cancer susceptibility" NATURE GENETICS, vol. 40, no. 3, March 2008 (2008-03), pages 316-321, XP002513956 ISSN: 1061-4036 *
NAM ET AL: "A Novel Serum Marker, Total Prostate Secretory Protein of 94 Amino Acids, Improves Prostate Cancer Detection and Helps Identify High Grade Cancers at Diagnosis" JOURNAL OF UROLOGY, BALTIMORE, MD, US, vol. 175, no. 4, 1 April 2006 (2006-04-01), pages 1291-1297, XP005363045 ISSN: 0022-5347 *
SCHAID D J: "The complex genetic epidemiology of prostate cancer" HUMAN MOLECULAR GENETICS, OXFORD UNIVERSITY PRESS, SURREY, vol. 13, no. REVIEW NR 1, 28 January 2004 (2004-01-28), pages R103-R121, XP002396337 ISSN: 0964-6906 *
THOMAS GILLES ET AL: "Multiple loci identified in a genome-wide association study of prostate cancer" NATURE GENETICS, vol. 40, no. 3, March 2008 (2008-03), pages 310-315, XP002513957 ISSN: 1061-4036 *

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US10703822B2 (en) 2008-06-04 2020-07-07 Modiquest B.V. Anti-inflammatory agents
US10260104B2 (en) 2010-07-27 2019-04-16 Genomic Health, Inc. Method for using gene expression to determine prognosis of prostate cancer
WO2012029080A1 (fr) * 2010-08-30 2012-03-08 Decode Genetics Ehf Variants de séquence associés à des taux d'antigène spécifique de la prostate
US9732389B2 (en) 2010-09-03 2017-08-15 Wake Forest University Health Sciences Methods and compositions for correlating genetic markers with prostate cancer risk
EP2611943A2 (fr) * 2010-09-03 2013-07-10 Wake Forest University Health Sciences Procédés et compositions pour la corrélation de marqueurs génétiques au risque de cancer de la prostate
EP2611943A4 (fr) * 2010-09-03 2014-01-08 Univ Wake Forest Health Sciences Procédés et compositions pour la corrélation de marqueurs génétiques au risque de cancer de la prostate
WO2012031207A2 (fr) 2010-09-03 2012-03-08 Wake Forest University Health Sciences Procédés et compositions pour la corrélation de marqueurs génétiques au risque de cancer de la prostate
US10443105B2 (en) 2010-09-03 2019-10-15 Wake Forest University Health Sciences Methods and compositions for correlating genetic markers with prostate cancer risk
US11421282B2 (en) 2010-09-03 2022-08-23 Wake Forest University Health Sciences Methods and compositions for correlating genetic markers with prostate cancer risk
US9534256B2 (en) 2011-01-06 2017-01-03 Wake Forest University Health Sciences Methods and compositions for correlating genetic markers with risk of aggressive prostate cancer
CN103060434A (zh) * 2012-10-19 2013-04-24 卫生部北京医院 一种预测前列腺癌易感性的试剂和方法
CN103060432A (zh) * 2012-10-19 2013-04-24 卫生部北京医院 一种预测前列腺癌易感性的方法和检测试剂盒
CN103432593A (zh) * 2013-08-01 2013-12-11 中山大学附属肿瘤医院 一种用于预防或治疗食管癌的药物组合物
CN103432593B (zh) * 2013-08-01 2015-04-15 中山大学附属肿瘤医院 一种用于预防或治疗食管癌的药物组合物

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