WO2023233945A1 - Procédé de test du cancer des voies biliaires - Google Patents

Procédé de test du cancer des voies biliaires Download PDF

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WO2023233945A1
WO2023233945A1 PCT/JP2023/017497 JP2023017497W WO2023233945A1 WO 2023233945 A1 WO2023233945 A1 WO 2023233945A1 JP 2023017497 W JP2023017497 W JP 2023017497W WO 2023233945 A1 WO2023233945 A1 WO 2023233945A1
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biliary tract
measured
tract cancer
mass
detection mode
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PCT/JP2023/017497
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Japanese (ja)
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隆士 石垣
眞由美 阿部
顕成 檜
広夫 内田
俊男 國料
隆史 水野
真輝 砂川
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株式会社日立ハイテク
国立大学法人東海国立大学機構
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/493—Physical analysis of biological material of liquid biological material urine

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  • the present invention relates to a method, kit, and device for determining biliary tract cancer in a subject based on measured values of urinary tumor markers.
  • Biliary tract cancer is a relatively common cancer in Japan, and the 5-year survival rate, which is an indicator of prognosis, is low, so it is desirable to detect and treat it early.
  • Blood CEA, CA19-9, etc. are known as tumor markers for biliary tract cancer for early detection, but their tumor specificity is low and their accuracy is not high.
  • blood tests are invasive and are essentially limited to tests performed at medical institutions.
  • Patent Documents 1 to 5 are reports in Patent Documents 1 to 5 as tumor markers for cancer such as biliary tract cancer.
  • Patent Document 1 mainly describes genes and proteomics as tumor markers.
  • Patent Documents 2 to 5 describe metabolites as tumor markers for cancers such as colon cancer, but do not describe the urinary tumor marker disclosed herein.
  • An object of the present invention is to provide a means and method for non-invasively and easily determining biliary tract cancer, which has been desired in the past.
  • the present inventor identified a group of markers related to biliary tract cancer, and used these markers alone or in combination to determine biliary tract cancer and predict risk. discovered that biliary tract cancer monitoring can be performed easily and non-invasively.
  • the present invention relates to a method, device, and kit for determining biliary tract cancer and/or monitoring biliary tract cancer in a subject by measuring urinary metabolites that are urinary tumor markers.
  • Specific embodiments include:
  • a method for determining biliary tract cancer in a subject comprising: measuring a urinary tumor marker in a urine sample from a subject, the urinary tumor marker being measured in cholate, chenodeoxycholate sulfate, LC/MS negative ion detection mode as a mass-to-charge ratio of 259.028; compound (C10H12O6S), glycochenodeoxycholic acid 3-sulfate, isoleucylhydroxyproline, pro-hydroxy-pro, kynurenine, 4-methoxyphenol sulfate, 5-hydroxylysine, trans-4-hydroxyproline, glycylleucine , glycocholate, compound measured as mass-to-charge ratio 197.068 in LC/MS negative ion detection mode (C7H10N4O3), compound measured as mass-to-charge ratio 509.277 in LC/MS negative ion detection mode (C28H38N4O5), 3- Hydroxykynurenine, glycocheno
  • a device for determining biliary tract cancer A measurement unit for measuring a urinary tumor marker in a urine sample, wherein the urinary tumor marker is cholate, chenodeoxycholate sulfate, and a compound measured as a mass-to-charge ratio of 259.028 in LC/MS negative ion detection mode.
  • a method for evaluating the effectiveness of biliary tract cancer treatment comprising: measuring a urinary tumor marker in a urine sample from a patient with biliary tract cancer treated with an investigational therapeutic agent or therapy, the urinary tumor marker being cholate, chenodeoxycholate sulfate; , Compound measured as mass-to-charge ratio 259.028 in LC/MS negative ion detection mode (C10H12O6S), glycochenodeoxycholic acid 3-sulfate, isoleucylhydroxyproline, pro-hydroxy-pro, kynurenine, 4-methoxyphenol sulfate , 5-hydroxylysine, trans-4-hydroxyproline, glycylleucine, glycocholate, compound measured as mass-to-charge ratio 197.068 in LC/MS negative ion detection mode (C7H10N4O3), LC/MS negative ion detection mode (C28H38N4O5), 3-hydroxykynurenine, glycocheno
  • the present invention provides a method, device, and kit for determining biliary tract cancer in a minimally invasive, simple, and low-cost manner. Since the test uses urine, the collection method in clinical settings is also extremely simple, greatly improving convenience for medical professionals. Therefore, the present invention is useful in fields such as biliary tract cancer diagnosis, testing, therapeutic evaluation, and drug discovery.
  • RF random forest
  • For biliary tract cancer they are a graph (A) showing the calculation results of predicted values when 10 types of markers are applied to the cancer test model, and a graph (B) showing the AUC of the cancer test model.
  • For biliary tract cancer they are a graph (A) showing the calculation results of predicted values when 10 types of markers are applied to the cancer test model, and a graph (B) showing the AUC of the cancer test model.
  • biliary tract cancer For biliary tract cancer, they are a graph (A) showing the calculation results of predicted values when 20 types of markers are applied to the cancer test model, and a graph (B) showing the AUC of the cancer test model.
  • biliary tract cancer For biliary tract cancer, they are a graph (A) showing the calculation results of predicted values when 20 types of markers are applied to the cancer test model, and a graph (B) showing the AUC of the cancer test model.
  • these are a graph (A) showing the calculation results of predicted values when six types of markers that are considered important are applied to the cancer testing model, and a graph (B) showing the AUC of the cancer testing model.
  • a graph (A) showing the calculation results of predicted values when three types of markers considered to be important are applied to the cancer testing model, and a graph (B) showing the AUC of the cancer testing model.
  • these are a graph (A) showing the calculation results of predicted values when two types of markers considered to be important are applied to the cancer testing model, and a graph (B) showing the AUC of the cancer testing model.
  • An example of the configuration of a device to which the present invention is applied is shown. This is a graph showing the top 20 metabolites when urinary metabolites related to the difference between biliary tract cancer and healthy individuals are ranked by random forest (RF).
  • a graph (A) showing the calculation results of predicted values when five types of markers considered to be important are applied to the cancer testing model, and a graph (B) showing the AUC of the cancer testing model.
  • the methods, devices, and kits provided by the present invention utilize novel urinary tumor markers and marker groups associated with biliary tract cancer.
  • This urinary tumor marker is a metabolite whose urinary level differs depending on the presence or absence of biliary tract cancer, so it can be used to detect biliary tract cancer, predict the risk of biliary tract cancer, and determine the stage of biliary tract cancer. It is useful for determining the prognosis of biliary tract cancer, monitoring biliary tract cancer, and/or monitoring the therapeutic effect on biliary tract cancer.
  • the method for determining biliary tract cancer according to the present invention includes the steps of measuring a urinary tumor marker in a urine sample derived from a subject, and determining biliary tract cancer in the subject based on the measurement results.
  • Biliary tract cancer refers to cancer (malignant tumor) that occurs in the bile tract, including intrahepatic bile duct cancer, extrahepatic bile duct cancer (portal bile duct cancer, distal bile duct cancer), gallbladder cancer, It is classified as papillary cancer. Biliary tract cancers are classified into primary, metastatic, and recurrent types, and are classified into stages based on the degree of progression and spread. Necessary treatments (surgery, chemotherapy, radiotherapy, immunotherapy, etc.) also differ depending on whether the disease is primary, metastatic, or recurrent, and the stage.
  • a urinary tumor marker associated with biliary tract cancer is measured.
  • the "urinary metabolites” or “urinary tumor markers” to be measured in the present invention refer to the urinary metabolites listed in Table 1 below. Urinary metabolites are more convenient as tumor markers because they are less affected by enzymes and are structurally stable compared to substances in the blood. Furthermore, since urine is used as a specimen, it can be easily collected from a subject, making it extremely easy to use for cancer screening. Furthermore, a "marker group” is a combination of two or more urinary tumor markers.
  • Measure means determining the relative abundance or absolute concentration of a metabolite in a urine sample. Relative abundance is the ratio of the measured intensity of a metabolite of interest to an intentionally added standard substance.
  • the absolute concentration is defined as a calibration curve (relationship between the concentration of the metabolite and the measured intensity of the metabolite) created in advance using the same metabolite for the target metabolite, and calculated from the measured intensity. This is a method to calculate absolute concentration.
  • “measuring a urinary tumor marker” may mean measuring a metabolite that is a urinary tumor marker, or a derivative or a derivative thereof.
  • Derivative and “derivative” refer to a substance derived from a metabolite that is a urinary tumor marker and a substance derived from the metabolite, respectively. “Derivatives” and “derivatives” include, but are not limited to, fragments of metabolites, modified metabolites, and the like.
  • the main urinary tumor markers used in the present invention are summarized in Table 1 below.
  • the "metabolite” column shows the name of a metabolite whose structure was found as a result of a database search, or the symbol and estimated chemical formula if the structure is unknown.
  • the estimated chemical formula is estimated from the "measured mass” and “measurement mode” and a metabolite database such as the Human Metabolome Database (HMDB).
  • HMDB Human Metabolome Database
  • the CAS registration number in Table 1 is the de facto standard for chemical substance IDs and is a number for identifying chemical substances, and the HMDB ID is the ID of HMDB, an online database of small and medium molecule metabolites in the human body.
  • the "Measurement mass” column shows the mass-to-charge ratio when detected by the detection means described in the "Measurement mode” column.
  • “Neg”, “Pos Early”, and “Polar” in the “Measurement mode” column are “negative ion detection mode of liquid chromatograph mass spectrometer (LC/MS)” and “liquid chromatograph mass spectrometer (LC/MS)”, respectively.
  • LC/MS pos early is also simply referred to as "positive ion detection mode of liquid chromatograph mass spectrometer (LC/MS).”
  • the measured mass in Table 1 is basically the mass of the ionized metabolite, with one proton added or lost, and the mass varies by ⁇ 1 from the original metabolite mass. However, depending on the measurement conditions, multiple protons, sodium, etc. may be added or lost, and the measured mass will vary accordingly. Alternatively, a mass spectrum of fragment ions obtained by imparting energy to the metabolite and causing it to cleave may be measured.
  • cholate as shown in Table 1 is measured. That is, a compound measured as a mass of 407.280 in LC/MS negative ion detection mode is measured.
  • chenodeoxycholic acid sulfate (2) shown in Table 1 is measured. That is, a compound measured as a mass of 235.118 in LC/MS negative ion detection mode is measured.
  • X-17686 (C10H12O6S) shown in Table 1 is measured. That is, a compound (C10H12O6S) whose mass is measured as 259.028 in LC/MS negative ion detection mode is measured.
  • glycochenodeoxycholic acid 3-sulfate as shown in Table 1 is measured. That is, a compound measured as a mass of 263.628 in LC/MS negative ion detection mode is measured.
  • isoleucylhydroxyproline as shown in Table 1 is measured. That is, a compound measured as a mass of 245.150 in LC/MS positive ion detection mode is measured.
  • pro-hydroxy-pro as shown in Table 1 is measured. That is, a compound measured as a mass of 229.118 in LC/MS positive ion detection mode is measured.
  • kynurenine as shown in Table 1 is measured. That is, a compound measured as a mass of 209.092 in LC/MS positive ion detection mode is measured.
  • 4-methoxyphenol sulfate as shown in Table 1 is measured. That is, a compound measured as a mass of 203.002 in LC/MS negative ion detection mode is measured.
  • 5-hydroxylysine as shown in Table 1 is measured. That is, a compound measured as a mass of 163.108 in LC/MS positive ion detection mode is measured.
  • trans-4-hydroxyproline shown in Table 1 is measured. That is, a compound whose mass is measured as 130.051 in LC/MS polar detection mode is measured.
  • glycylleucine as shown in Table 1 is measured. That is, a compound measured as a mass of 189.123 in LC/MS positive ion detection mode is measured.
  • the glycocholates shown in Table 1 are measured. That is, a compound measured as a mass of 464.302 in LC/MS negative ion detection mode is measured.
  • X-13728 (C7H10N4O3) shown in Table 1 is measured. That is, a compound (C7H10N4O3) whose mass is measured as 197.068 in LC/MS negative ion detection mode is measured.
  • X-21851 (C28H38N4O5) shown in Table 1 is measured. That is, a compound (C28H38N4O5) measured as a mass of 509.277 in LC/MS negative ion detection mode is measured.
  • 3-hydroxykynurenine as shown in Table 1 is measured. That is, a compound measured as a mass of 225.087 in LC/MS positive ion detection mode is measured.
  • the glycochenodeoxycholates shown in Table 1 are measured. That is, a compound measured as a mass of 448.307 in LC/MS negative ion detection mode is measured.
  • isoleucylglycine shown in Table 1 is measured. That is, a compound measured as a mass of 187.116 in LC/MS negative ion detection mode is measured.
  • the phenylalanyl hydroxyproline shown in Table 1 is measured. That is, a compound measured as a mass of 279.134 in LC/MS positive ion detection mode is measured.
  • 4-hydroxyphenylpyruvate as shown in Table 1 is measured. That is, a compound measured as having a mass of 179.035 in LC/MS negative ion detection mode is measured.
  • lactate as shown in Table 1 is measured. That is, a compound whose mass is measured as 89.024 in LC/MS polar detection mode is measured.
  • cyclo(pro-hydroxypro) as shown in Table 1 is measured. That is, a compound measured as a mass of 211.108 in LC/MS positive ion detection mode is measured.
  • tryptophan as shown in Table 1 is measured. That is, a compound measured as a mass of 205.097 in LC/MS positive ion detection mode is measured.
  • N6-acetyl lysine as shown in Table 1 is measured. That is, a compound measured as a mass of 187.109 in LC/MS polar detection mode is measured.
  • gamma-glutamylphenylalanine as shown in Table 1 is measured. That is, a compound measured as a mass of 295.129 in LC/MS positive ion detection mode is measured.
  • leucyl hydroxyproline as shown in Table 1 is measured. That is, a compound measured as a mass of 245.150 in LC/MS positive ion detection mode is measured.
  • X-18887 (C14H23N3O6) shown in Table 1 is measured. That is, a compound (C14H23N3O6) whose mass is measured as 328.152 in LC/MS negative ion detection mode is measured.
  • X-24475 (C6H11NO3) shown in Table 1 is measured. That is, a compound (C6H11NO3) whose mass is measured as 146.081 in LC/MS positive ion detection mode is measured.
  • the androsterone glucuronides shown in Table 1 are measured. That is, a compound measured as a mass of 465.249 in LC/MS negative ion detection mode is measured.
  • the 3-hydroxyanthranilates shown in Table 1 are measured. That is, a compound measured as a mass of 154.050 in LC/MS positive ion detection mode is measured.
  • 11 beta-hydroxyandrosterone glucuronide as shown in Table 1 is measured. That is, a compound measured as a mass of 481.244 in LC/MS negative ion detection mode is measured.
  • cystathionine as shown in Table 1 is measured. That is, a compound measured as a mass of 221.060 in LC/MS positive ion detection mode is measured.
  • carnosine as shown in Table 1 is measured. That is, a compound measured as a mass of 227.114 in LC/MS positive ion detection mode is measured.
  • proline as shown in Table 1 is measured. That is, a compound measured as a mass of 116.071 in LC/MS positive ion detection mode is measured.
  • anserine as shown in Table 1 is measured. That is, a compound measured as a mass of 239.115 in LC/MS negative ion detection mode is measured.
  • arabitol/xylitol as shown in Table 1 is measured. That is, a compound whose mass is measured as 151.061 in LC/MS polar detection mode is measured.
  • 3-hydroxy-2-ethylpropionate as shown in Table 1 is measured. That is, a compound whose mass is measured as 117.056 in LC/MS polar detection mode is measured.
  • the 2R,3R-dihydroxybutyrate shown in Table 1 is measured. That is, a compound whose mass is measured as 119.035 in LC/MS polar detection mode is measured.
  • gamma-glutamyltyrosine as shown in Table 1 is measured. That is, a compound measured as a mass of 311.124 in LC/MS negative ion detection mode is measured.
  • 1-methyladenine as shown in Table 1 is measured. That is, a compound measured as having a mass of 150.077 in LC/MS positive ion detection mode is measured.
  • the dihydroorotonic acid shown in Table 1 is measured. That is, a compound whose mass is measured as 157.026 in LC/MS polar detection mode is measured.
  • alanine as shown in Table 1 is measured. That is, a compound measured as having a mass of 90.055 in LC/MS positive ion detection mode is measured.
  • 17 alpha-hydroxypregnenolone glucuronide as shown in Table 1 is measured. That is, a compound measured as a mass of 509.276 in LC/MS negative ion detection mode is measured.
  • the mass spectrometer used to analyze the metabolites shown in Table 1 has a very high resolution, so it is possible to measure mass to about five decimal places. However, taking into account measurement errors, Table 1 is It is written in 3 digits after the decimal point. Furthermore, when using a mass spectrometer with low resolution, an integer mass or a mass of one or two digits after the decimal point is measured.
  • At least one of the urinary tumor markers shown in Table 1 can be used to determine biliary tract cancer and monitor the effects of treatment.
  • the present invention by using at least two or three or more urinary tumor markers in combination, more accurate and precise determination and monitoring of the effectiveness of treatment are possible.
  • at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, At least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or more can be combined.
  • the combination of markers is not particularly limited.
  • at least three urinary tumor markers are measured.
  • the urinary tumor markers shown in Table 1 can be used alone to determine biliary tract cancer.
  • the marker includes at least glycochenodeoxycholic acid 3-sulfate, or glycocholate, or 4-hydroxyphenylpyruvate.
  • Yobs is the measured value
  • Ycalc is the calculated value by OPLS
  • Ypred is the predicted value when cross-validated, represents the average value.
  • Cross-validation refers to a method in which data is divided, a part of it is analyzed first, and the remaining part is used to test the analysis to verify and confirm the validity of the analysis itself. According to this, it can be said that the closer the value of the accuracy variable R2Y is to 1, the higher the accuracy of the model is, and the closer the Q2 value of the predictor variable is to 1, the higher the predictiveness of the model is. It is thought that by using a combination with high values of the accuracy variable and the predictive variable for biliary tract cancer determination, more accurate determination will be possible.
  • the combination of urinary tumor markers is determined based on the type, sex, and age of the subject, the determination of biliary tract cancer, and the follow-up of subjects at high risk (e.g., based on family history) or subjects with no abnormalities (monitoring of biliary tract cancer). ), or can be selected as appropriate depending on the purpose including treatment monitoring.
  • the partial least squares method which is a type of multivariate analysis, particularly OPLS-DA can be used.
  • multivariate analysis it may be difficult to understand the characteristics of the data if multidimensional data is used as is, so it may be necessary to reduce it to 2D or 3D data for visual visualization.
  • analysis methods known in the art such as principal component analysis.
  • Urine sample refers to urine collected from a subject and a sample obtained by processing the urine (for example, urine to which a preservative such as toluene, xylene, or hydrochloric acid has been added).
  • the target is human urine. Since metabolic activity in the human body is assumed to differ depending on race, etc., monogoroid people, including Japanese, who are the subjects of analysis of the present invention, are preferred, but not limited thereto. For example, it may be during mass screening such as health checkups or cancer tests, during additional examinations after such mass screening, or before and after surgery at a hospital, or during treatment such as chemotherapy or radiation. Good too. Furthermore, even in the same individual, the concentration of metabolites in urine easily varies depending on the timing of urine collection, water intake, etc.
  • the amount of creatinine in the same urine or the osmolality (osmolality) of the same urine is measured and the amount of each metabolite is divided. Standardize.
  • the urinary metabolite amount hereinafter basically means a standardized amount.
  • Measuring a urinary tumor marker means measuring its amount or concentration in a urine sample, preferably semi-quantitatively or quantitatively, and the amount may be an absolute amount or a relative amount. There may be. Measurements can be made directly or indirectly. Direct measurement involves determining the amount or concentration of a urinary metabolite based on a signal that directly correlates with the number of molecules present in the sample. Such signals are based, for example, on certain physical or chemical properties of the urinary metabolites. Indirect measurements are measurements of signals obtained from secondary components (ie components other than urinary metabolites), such as ligands, labels or enzymatic reaction products.
  • secondary components ie components other than urinary metabolites
  • a urinary tumor marker that is, a urinary metabolite is measured, but the measurement method is not particularly limited, and any method or means known in the art can be used.
  • measurement of urinary tumor markers can be performed by means of measuring physical or chemical properties specific to urinary metabolites, such as precise molecular weight or NMR spectra.
  • means for measuring metabolites in urine include analysis devices such as a mass spectrometer, an NMR analyzer, a two-dimensional electrophoresis device, a chromatograph, and a liquid chromatography mass spectrometer (LC/MS). Although these analyzers may be used alone to measure a urinary tumor marker, a plurality of analyzers may be used to measure a urinary tumor marker.
  • a reagent for detecting a metabolite to be measured such as an immunoreaction reagent or an enzyme reaction reagent, is available, such a reagent can be used to measure the metabolite in urine.
  • urinary tumor marker contained in the urine sample collected from the subject and determine biliary tract cancer in the subject based on the results. Additionally, urinary tumor markers may be measured in urine samples taken from the subject at multiple time points.
  • the presence and progression of biliary tract cancer can be determined at an early stage, which is useful for detailed examinations and determining treatment strategies. If it becomes possible to diagnose biliary tract cancer with a simple test, it can be expected to not only provide treatment but also prevent the risk of invasion caused by the test. Patients will be able to receive early treatment for biliary tract cancer, and those at high risk will be able to be monitored for the development of biliary tract cancer. Furthermore, the effect of biliary tract cancer treatment can be monitored, and it becomes possible to consider stopping, continuing, or changing the treatment depending on the treatment effect.
  • the method for determining biliary tract cancer of the present invention can be carried out easily and conveniently by using a kit and/or device equipped with a means for measuring a urinary tumor marker, which is a urinary metabolite.
  • the kit for determining biliary tract cancer according to the present invention includes at least a means for measuring at least one (preferably at least three) of the urinary tumor markers shown in Table 1 above.
  • kits of the present invention are a mass spectrometry reagent set, which includes, for example, an isotope labeling reagent, a fractionation minicolumn, a buffer solution, and the like.
  • a kit is an immunoreaction reagent set, which includes, for example, a substrate on which a primary antibody is immobilized, a secondary antibody, and the like.
  • an enzyme reaction reagent set is composed of, for example, an enzyme, a buffer solution, and the like.
  • the kit of the present invention may include an instruction manual describing the procedure and protocol for implementing the method of the present invention, a table showing reference values or reference ranges used in determining biliary tract cancer, and the like.
  • kit of the present invention may be provided individually or within a single container.
  • the kit of the invention contains all of the components necessary to carry out the method of the invention, eg as components in adjusted concentrations, ready for immediate use.
  • the biliary tract cancer determination device includes the following means: a measurement unit that measures at least one (preferably at least three) of the urinary tumor markers shown in Table 1 above in the urine sample; a comparison unit that compares the measurement value of the urinary tumor marker measured by the measurement unit with a reference value or a previous measurement value; A determination unit that determines biliary tract cancer from the comparison results obtained by the comparison unit.
  • the biliary tract cancer determination device includes the following means: a measurement unit that measures at least one (preferably at least three) of the urinary tumor markers shown in Table 1 above in the urine sample; From the explanatory variables measured by the above measurement unit (the amount or concentration of urinary tumor markers, or the observed ion intensity ratio of urinary tumor markers that increases or decreases in biliary tract cancer patients, for example, compared to benign or no abnormalities) The calculated value of the objective variable (biliary tract cancer, abnormal a comparison unit that compares it with a reference value that is an index (indicating whether there is no A determination unit that determines biliary tract cancer from the comparison results obtained by the comparison unit.
  • the apparatus of the present invention is preferably a system in which the measuring section, the comparing section, and the determining section described above are operably connected to each other so that the method of the present invention can be carried out.
  • One embodiment of the device of the invention is shown in FIG.
  • the measurement unit includes a means for measuring a urinary tumor marker in a urine sample as described above, such as a mass spectrometer, an NMR analyzer, a two-dimensional electrophoresis device, a chromatograph, a liquid chromatography mass Equipped with analysis equipment such as analysis (LC/MS) equipment.
  • a means for measuring a urinary tumor marker in a urine sample as described above such as a mass spectrometer, an NMR analyzer, a two-dimensional electrophoresis device, a chromatograph, a liquid chromatography mass Equipped with analysis equipment such as analysis (LC/MS) equipment.
  • LC/MS analysis
  • the measurement unit includes a data analysis unit consisting of a computer and software that processes the measurement values obtained from the above-mentioned analysis device or the like.
  • the data analysis unit calculates the amount or concentration of the urinary tumor marker contained in the urine sample by referring to data such as a calibration curve based on the measurement values obtained from the above-mentioned analyzer or the like.
  • the data analysis unit analyzes the explanatory variables measured by the measurement unit (the amount or concentration of urinary tumor markers, or whether they increase or decrease in patients with biliary tract cancer relative to benign or no abnormality, for example).
  • the calculated value of the objective variable (whether there is biliary tract cancer or no abnormality) is calculated based on the cancer test model obtained by multivariate analysis from the observed ion intensity ratio of the urinary tumor marker. Calculate the index (indicating whether The data analysis section can include, for example, a signal display section, a unit for analyzing measured values, a computer unit, etc.
  • the comparison section reads out a reference value regarding the amount or concentration of the urinary tumor marker from a storage device (database), etc., and compares the measurement value of the urinary tumor marker measured by the measurement section with the reference value.
  • the comparison section reads the reference value of the target variable from a storage device (database), etc., and compares the calculated value of the target variable obtained by the measurement section with the reference value.
  • the comparison section selects and reads an appropriate reference value according to the type of urinary tumor marker.
  • the comparison section reads the previous measurement value from a storage device (database), etc., and compares it with the measurement value of the urinary tumor marker measured by the measurement section.
  • the determination section determines whether the measurement value of the urinary tumor marker is compared with the reference value in the comparison section, or based on the result of comparing the measurement value of the urinary tumor marker at a plurality of time points in the comparison section. , determine biliary tract cancer.
  • the determination section is based on the results of comparing the calculated value of the objective variable and the reference value in the comparing section, or the results of comparing the calculated values of the objective variable at multiple points in time in the comparing section. Based on this, biliary tract cancer is determined.
  • the determination unit acquires information indicating the presence of biliary tract cancer in the subject, the stage of biliary tract cancer, and whether there is any abnormality.
  • Preferred devices are those that can be used without the knowledge of a specialized clinician, such as electronic devices that simply require the addition of a sample.
  • the determination unit determines that the subject may have biliary tract cancer when the urinary tumor marker is equal to or higher than the reference value or the previous measurement value. For example, if the urinary tumor marker is lower than the reference value or the previous measurement value, the determination unit determines that there is a possibility that the subject has no abnormality.
  • the device of the present invention may further include a data storage section, a data output/display section, and the like.
  • determination of biliary tract cancer means not only detecting biliary tract cancer in a subject, but also predicting the risk of biliary tract cancer in a subject, to determine the stage of biliary tract cancer, to determine the prognosis of biliary tract cancer in a subject, to monitor biliary tract cancer in a subject, to monitor the effect of treatment for biliary tract cancer existing in a subject, and to monitor biliary tract cancer in a subject. This meaning includes assisting in diagnosis. Furthermore, in the present invention, “determination” includes continuous monitoring of biliary tract cancer that has already been detected or diagnosed, and confirmation of the detection or diagnosis of biliary tract cancer that has already been performed.
  • determination by the biliary tract cancer determination method, determination kit, and determination device according to the present invention is intended to be able to determine a statistically significant proportion of subjects. Therefore, “determination” by the biliary tract cancer determination method, determination kit, and determination device according to the present invention includes cases where correct results are not always obtained for all (ie, 100%) of the subjects. Statistically significant proportions can be determined using a variety of well-known statistical evaluation tools, such as determining confidence intervals, determining p-values, Student's t-test, Mann-Whitney test, and the like. A preferred confidence interval is at least 90%. The p-value is preferably 0.1, 0.01, 0.05, 0.005 or 0.0001. More preferably, at least 60%, at least 80%, or at least 90% of the subjects can be appropriately determined by the biliary tract cancer determination method, determination kit, and determination device according to the present invention.
  • a urinary tumor marker is measured in a subject's urine sample and the measurement is compared to a baseline or previous measurement.
  • each urinary tumor marker may be compared with its reference value or previous measurement value, or the calculated value of the target variable obtained by multivariate analysis may be calculated. , it may be compared with a reference value or a previous measurement value.
  • the standard is the amount or concentration of a urinary tumor marker related to biliary tract cancer, or the range of the amount or concentration, or the amount or concentration of a urinary tumor marker that is an indicator of no abnormality, or the amount or concentration of the urinary tumor marker. range of concentrations.
  • the calculated value of the objective variable that identifies biliary tract cancer/no abnormality becomes the reference value.
  • the reference value can be derived from healthy subjects (population) or low-risk biliary tract cancer subjects (population).
  • the reference value may be derived from patients (patient populations) who have biliary tract cancer (e.g., a certain stage of biliary tract cancer) or who have biliary tract cancer with a particular prognosis. .
  • the reference value applied to an individual subject may vary depending on various physiological parameters such as the species, age, and sex of the subject animal.
  • the correlation between the amount or concentration of a urinary tumor marker and the presence of biliary tract cancer or a specific prognosis is recorded as a database.
  • the measured value of the urinary tumor marker in the urine sample can then be compared with the reference value in the database.
  • Such a database is useful as an indicator of the presence or absence of biliary tract cancer (or a specific stage of biliary tract cancer), or a reference value or reference range that is an indicator of prognosis.
  • the amount or concentration of the urinary tumor markers shown in Table 1 differs depending on the presence or absence of biliary tract cancer, and the amount or concentration changes depending on the presence of biliary tract cancer and before or after the start of treatment.
  • the markers shown in Table 1 have increased amounts or concentrations in patients with biliary tract cancer compared to subjects without biliary tract cancer. Therefore, if the marker shown in Table 1 is higher than the reference value derived from the normal population (subjects without biliary tract cancer) or equal to or higher than the reference value derived from the patient population with biliary tract cancer.
  • the subject may have or is at high risk of biliary tract cancer.
  • the threshold value of the predicted value is not limited to 0 and may be varied.
  • the magnitude of the predicted value may be quantitatively associated with the risk (probability) of cancer without clearly defining the threshold value.
  • a urine sample is collected from the subject at multiple time points, a urinary tumor marker is determined in the urine sample at each time point, and the urinary tumor marker measurements are compared at each time point. do. More specifically, the amount or concentration of the urinary tumor marker at the first time point (a) is compared with the amount or concentration of the urinary tumor marker at the second time point (b).
  • the calculated value of one component at the first time point and the calculated value at the second time point are compared. Measurements are taken at least 2, 3, 4, 5, 10, 15, 20, 30 or more times over time, e.g. 1 day, 2 days, 5 days, 1 week.
  • the urinary tumor marker used in the present invention can be used to monitor the effect of treatment (therapeutic agent or treatment method) on biliary tract cancer in a subject.
  • a urine sample is collected from a patient with biliary tract cancer, and urinary tumor markers in the urine sample are measured before receiving treatment with a therapeutic agent or treatment method.
  • a urine sample is collected at an appropriate time and urinary tumor markers are measured in the urine sample. For example, immediately after treatment, 30 minutes, 1 hour, 3 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours (1 day), 2-10 days, 10-20 Collect urine samples after 1 day, 20 to 30 days, and 1 month to 6 months. Measurement of urinary tumor markers in urine samples can be performed in the same manner as described above. By measuring urinary tumor markers before and after treatment, it becomes possible to monitor the effectiveness of treatment with the therapeutic agent or method. Based on the results of monitoring, it helps to consider stopping, continuing, or changing treatment.
  • the method for determining biliary tract cancer may be performed in combination with other conventionally known methods for diagnosing biliary tract cancer.
  • Such known methods for diagnosing biliary tract cancer include blood tests (measurement of blood cancer markers, liver function tests, etc.), image tests (such as abdominal ultrasound, computed tomography (CT), MRI), Positron CT (PET), etc.), endoscopy, and pathological examinations such as biopsy or cytology.
  • the doctor can diagnose the subject's biliary tract cancer and take appropriate treatment. That is, the present invention also relates to a method for determining and treating biliary tract cancer in a subject. For example, if biliary tract cancer is determined in a subject according to the method of the present invention and it is evaluated that the subject is likely to have biliary tract cancer, the subject is treated for biliary tract cancer or Take measures to prevent progression. In addition, if it is assessed that the stage of biliary tract cancer in the subject is advanced or that the prognosis of biliary tract cancer is likely to be poor, treatment may be continued or, if necessary, a change in treatment method may be considered. do.
  • urinary tumor markers may be measured over time to avoid excessive testing and treatment. May be monitored for biliary tract cancer. Further, if it is evaluated that there is a high possibility that biliary tract cancer exists in the subject, other biliary tract cancer diagnostic methods such as those described above are performed to confirm the presence of biliary tract cancer. Furthermore, based on the evaluation results before and after the treatment, the effectiveness of the treatment is monitored and a decision is made to stop, continue, or change the treatment. Furthermore, if it is determined that there is no abnormality, urinary tumor markers can be measured over time to monitor the progress.
  • biliary tract cancer For biliary tract cancer, surgery (surgical resection), chemotherapy, radiation therapy, immunotherapy, proton beam therapy, heavy particle beam therapy, etc. can be performed alone or in appropriate combinations. Treatment for biliary tract cancer can be selected appropriately by those skilled in the art, taking into consideration the type, stage, malignancy, gender, age and condition of biliary tract cancer, responsiveness to treatment, genetic polymorphisms (SNPs), etc. can do.
  • SNPs genetic polymorphisms
  • the testing center provides guidance on cancer testing in response to requests from test subjects.
  • the test subject may select the number of biomarkers for the test.
  • the number of biomarkers includes 1 to 3 types of urinary tumor markers. This can also be used as a pan-cancer test (analyzing various cancers at once) in combination with other biomarkers.
  • the testing center hands the test subject the test kit necessary for urine collection. Send by mail, etc. as necessary. After receiving the test kit, the person to be tested hands or sends the specimen to the test center.
  • samples are frozen and stored at approximately -80°C for subsequent testing as needed.
  • storage at -80°C is not the only option, but frozen storage at approximately -5°C and refrigerated storage at approximately 5°C are recommended. , room temperature storage, etc.
  • the testing center performs a primary test and sends the test results to the person being tested.
  • the person to be tested may apply for a secondary test depending on the content, or may receive a more detailed diagnosis. This makes it possible to confirm the suspicion of biliary tract cancer in the primary examination and furthermore to identify the stage of biliary tract cancer.
  • the urinary tumor marker used in the present invention can be used to evaluate the effectiveness of biliary tract cancer treatment (therapeutic drug or treatment method) or to screen therapeutic drug candidates for biliary tract cancer.
  • a method for evaluating the effectiveness of biliary tract cancer treatment or a method for screening therapeutic drug candidates for biliary tract cancer includes: (a) measuring a urinary tumor marker in a urine sample from an animal with biliary tract cancer treated with the investigational therapeutic agent or therapy; (b) It includes the step of evaluating the effectiveness of the test drug or treatment method for biliary tract cancer based on the measurement results in (a).
  • a urine sample is collected from a patient with biliary tract cancer or a human without biliary tract cancer, and urinary tumor markers in the urine sample are measured.
  • a urine sample is collected from a person with biliary tract cancer and urinary tumor markers are measured in the urine sample prior to treatment with the test therapeutic agent or therapy.
  • urine samples are collected at appropriate times and urinary tumor markers are measured in the urine samples. For example, immediately after treatment, 30 minutes, 1 hour, 3 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours (1 day), 2-10 days, 10-20 Collect urine samples after 1 day, 20 to 30 days, and 1 month to 6 months. Measurement of urinary tumor markers in urine samples and determination of biliary tract cancer can be performed in the same manner as described above.
  • test therapeutic drug or treatment method to be evaluated or screened is not particularly limited.
  • the test therapeutic agent or therapy may include any material agent, specifically a naturally occurring molecule, such as an amino acid, a peptide, an oligopeptide, a polypeptide, a protein, a nucleic acid, a lipid, a carbohydrate (such as a sugar), steroids, glycopeptides, glycoproteins, proteoglycans, etc.; synthetic analogs or derivatives of naturally occurring molecules, such as peptidomimetics, nucleic acid molecules (aptamers, antisense nucleic acids, double-stranded RNA (RNAi), etc.); naturally occurring and mixtures thereof.
  • the therapeutic agent or treatment method may be a single substance, a complex composed of multiple substances, food, diet, or the like.
  • the test therapeutic agent or treatment method may include radiation, ultraviolet light, etc. in addition to the above-mentioned physical factors.
  • test therapeutic drug or treatment method can be examined under several conditions. Such conditions include the time or duration, amount (large or small), number of times, etc., of treatment with the test therapeutic agent or treatment method. For example, multiple doses can be established by preparing a dilution series of the test therapeutic agent. Furthermore, when examining additive effects, synergistic effects, etc. of multiple test therapeutic agents or treatments, the therapeutic agents or treatments may be used in combination.
  • the fact that the measured value after treatment is lower than the measured value before treatment means that the test drug or treatment is effective for the disappearance of biliary tract cancer, Indicates that the drug shrinks cancer, improves symptoms caused by biliary tract cancer, halts the progression of biliary tract cancer, or is effective.
  • the measured value after treatment is higher than the measured value before treatment or is not significantly different from the measured value before treatment, indicating that the test therapeutic agent or treatment method is not effective in treating biliary tract cancer.
  • Example 1 Comprehensive analysis of urinary metabolites related to biliary tract cancer At Nagoya University Hospital, permission was obtained from 27 patients with biliary tract cancer before tumor resection, 2 weeks after tumor resection, and 4 weeks after tumor resection.
  • Urine samples were collected at the end of the week (62 samples in total).
  • Patient information includes sample ID, sample collection date, age, gender, pre- and postoperative status, osmolarity, prognosis, diagnosis name, surgical method, histopathological type, pathological margin, pathological lymph node metastasis, stage, intraoperative blood transfusion, and medical history. Information regarding medical history, other marker measurements, etc. was recorded.
  • the specific breakdown of urine samples is as follows.
  • LC/MS liquid chromatography mass spectrometer
  • metabolites are identified using a database, that is, peak annotation is performed. If a metabolite not registered in the database is detected, structure estimation may be performed using tandem mass spectrometry (MS/MS), which actively generates fragment ions from target ions. Although it is not always possible to clearly estimate the structure using the MS/MS method, it is much easier to estimate the structure than isolating the target component and analyzing it using a nuclear magnetic resonance apparatus (NMR). Once candidate substances have been narrowed down using the MS/MS method, they are actually synthesized and their mass spectra and MS/MS spectra are compared to confirm the estimated structure.
  • MS/MS tandem mass spectrometry
  • PCA principal component analysis
  • Example 2 ROC curves were determined for the top 20 RF markers identified in Example 1 before and after surgery (with or without tumor), and AUC was determined. The results are shown in the table below.
  • the AUC value represents the discrimination ability for biliary tract cancer when the indicated marker is used alone. The closer the AUC value is to 1, the higher the discrimination ability is, and generally, an AUC value of 0.7 or higher can be considered a good model or a good discrimination ability.
  • Example 3 Construction of a cancer test model that combines multiple markers A cancer test model that combines multiple markers identified in Example 1 was constructed.
  • explanatory variables representing the fit to the training data used for model construction
  • predictor variables representing the predictive performance of the model (leave-one-out cross-validation). Verification
  • a cancer testing model was determined using the following indicators using the OPLS discriminant analysis method.
  • Yobs is the measured value
  • Ycalc is the calculated value by OPLS
  • Ypred is the predicted value when cross-validated, represents the average value.
  • Cross-validation refers to a method in which data is divided, a part of it is analyzed first, and the remaining part is used to test the analysis to verify and confirm the validity of the analysis itself.
  • the explanatory variable R2Y value indicates the fit to the training data used for model construction, and the closer it is to 1, the higher the model accuracy
  • the predictor variable Q2 value indicates the predictive performance of the model (leave-one-out cross -validation (leave-one-out cross-validation), the closer it is to 1, the more predictive the model is.
  • the cancer test model is, for example, when five types of markers are used, the concentration of each marker in the urine sample or the intensity of ions corresponding to each marker (actually, the mass chromatogram obtained by LC/MS measurement).
  • the prediction formula ⁇ x (marker 1 intensity) + ⁇ x (marker 2 intensity) + ⁇ x (marker 3 intensity) + ⁇ x (marker 4 intensity) + ⁇ x (marker 5 intensity) + ⁇ ( ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ are constants) are used to determine the risk of cancer. Specifically, the higher the predicted value, the higher the risk of cancer, and the lower the predicted value, the lower the risk of cancer. When determining whether cancer or normality is true or false, the threshold value of the predicted value is appropriately set.
  • the cancer testing model was evaluated using the OPLS discriminant analysis method for the top 10 or top 20 RF markers identified in Example 1. Specifically, we constructed cancer testing models for the following six areas. In Figures 2 to 8, white bar graphs indicate urine samples collected before biliary tract cancer resection, black bar graphs indicate urine samples collected 2 weeks after surgery, and diagonal bar graphs indicate urine samples collected 4 weeks after surgery. Shows the urine specimen collected in .
  • a model was constructed using the top 10 RF markers preoperatively versus 2 weeks postoperatively, and applied to specimens 4 weeks postoperatively. The results are shown in Figure 2, A (predicted value) and B (AUC). The diagonally lined bar graph is the test sample.
  • a model was constructed using the top 20 RF markers before surgery versus 2 weeks after surgery, and applied to specimens 4 weeks after surgery. The results are shown in Figure 4, A (predicted value) and B (AUC). The diagonally lined bar graph is the test sample.
  • a model was constructed using the top 20 RF markers before surgery versus 4 weeks after surgery, and applied to specimens 2 weeks after surgery. The results are shown in Figure 5, A (predicted value) and B (AUC). The black bar graph is the test sample.
  • markers considered to be particularly important were used to construct a model preoperatively versus postoperatively (both 2 weeks and 4 weeks). These six markers are metabolites that have a high ability to distinguish between biliary tract cancer and healthy individuals, as described below (Example 4).
  • glycochenodeoxycholate 3-sulfate (Table 3: 4th place, Table 6: 1st place), glycocholate (Table 3: 12th place, Table 6: 2nd place), 4-hydroxyphenylpyruvate (Table 3: 19th place, Table 6 : 6th place), glycochenodeoxycholate (Table 3: 16th place, Table 6: 9th place), trans-4-hydroxyproline (Table 3: 10th place, Table 6: 12th place), kynurenine (Table 3: 7th place, Table 6: 18th place).
  • A predicted value
  • B AUC
  • the black bars are postoperative specimens (both 2 and 4 weeks).
  • R2Y 0.447
  • predictive variable Q2 0.359
  • RF markers three markers considered to be particularly important were used to construct a model preoperatively versus postoperatively (both 2 weeks and 4 weeks). These three markers are metabolites that have a high ability to distinguish between biliary tract cancer and healthy individuals, as will be described later (Example 4). Specifically, glycochenodeoxycholate 3-sulfate (Table 3: 4th place, Table 6: 1st place), glycocholate (Table 3: 12th place, Table 6: 2nd place), 4-hydroxyphenylpyruvate (Table 3: 19th place, Table 6 :6th place). The results are shown in A (predicted value) and B (AUC) in FIG. Here, the black bars are postoperative specimens (both 2 and 4 weeks).
  • markers considered to be particularly important were used to build a model preoperatively versus postoperatively (both 2 weeks and 4 weeks). These two markers are metabolites that have a high ability to distinguish between biliary tract cancer and healthy individuals, as described below (Example 4). Specifically, they are glycochenodeoxycholate 3-sulfate (Table 3: 4th place, Table 6: 1st place) and glycocholate (Table 3: 12th place, Table 6: 2nd place). The results are shown in Figure 8, A (predicted value) and B (AUC). Here, the black bars are postoperative specimens (both 2 and 4 weeks).
  • Example 4 Comprehensive analysis of urinary metabolites by comparison of biliary tract cancer patients and healthy subjects With permission from 25 biliary tract cancer patients, urine samples were collected before tumor resection. In addition, as a control group, urine samples were collected from 25 people who were found to be healthy through medical examinations, with their permission. The specific breakdown of urine samples is as follows.
  • LC/MS liquid chromatography mass spectrometer
  • metabolites are identified using a database, that is, peak annotation is performed. If a metabolite not registered in the database is detected, structure estimation may be performed using tandem mass spectrometry (MS/MS), which actively generates fragment ions from target ions. Although it is not always possible to clearly estimate the structure using the MS/MS method, it is much easier to estimate the structure than isolating the target component and analyzing it using a nuclear magnetic resonance apparatus (NMR). Once candidate substances have been narrowed down using the MS/MS method, they are actually synthesized and their mass spectra and MS/MS spectra are compared to confirm the estimated structure.
  • MS/MS tandem mass spectrometry
  • RF random forest analysis
  • Example 5 The cancer test model was evaluated using the OPLS discriminant analysis method for the top 20, top 10, or top 5 RF markers identified in Example 4. Specifically, we constructed cancer testing models for the following three areas. In Figures 11 to 13, white bar graphs indicate urine samples from biliary tract cancer patients (before tumor resection), and black bar graphs indicate urine samples from healthy individuals.

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Abstract

La présente invention concerne un moyen et un procédé pour détecter un cancer des voies biliaires d'une manière non invasive et simple. Spécifiquement, la présente invention concerne un procédé, un dispositif et un kit pour détecter un cancer des voies biliaires chez un sujet par mesure d'un marqueur tumoral dans l'urine à partir d'un échantillon d'urine provenant d'un sujet.
PCT/JP2023/017497 2022-06-03 2023-05-10 Procédé de test du cancer des voies biliaires WO2023233945A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011099858A (ja) * 2009-11-06 2011-05-19 Chiba Univ 胆道がんの新規バイオマーカー
WO2017213246A1 (fr) * 2016-06-10 2017-12-14 株式会社日立製作所 Procédé de diagnostic de maladie basé sur un métabolite dans l'urine
JP2019105456A (ja) * 2017-12-08 2019-06-27 株式会社日立製作所 尿中代謝物におけるバイオマーカー探索法
WO2019131552A1 (fr) * 2017-12-27 2019-07-04 国立大学法人熊本大学 Biomarqueurs pour la détermination d'un cancer tel que le cancer du pancréas

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011099858A (ja) * 2009-11-06 2011-05-19 Chiba Univ 胆道がんの新規バイオマーカー
WO2017213246A1 (fr) * 2016-06-10 2017-12-14 株式会社日立製作所 Procédé de diagnostic de maladie basé sur un métabolite dans l'urine
JP2019105456A (ja) * 2017-12-08 2019-06-27 株式会社日立製作所 尿中代謝物におけるバイオマーカー探索法
WO2019131552A1 (fr) * 2017-12-27 2019-07-04 国立大学法人熊本大学 Biomarqueurs pour la détermination d'un cancer tel que le cancer du pancréas

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ALSALEH MUNIRAH, LEFTLEY ZOE, O’CONNOR THOMAS, HUGHES THOMAS, BARBERA THOMAS A., KOOMSON LARRY K., ZABRON ABIGAIL, REEVES HELEN, C: "Mapping of population disparities in the cholangiocarcinoma urinary metabolome", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 11, no. 1, US , XP093116586, ISSN: 2045-2322, DOI: 10.1038/s41598-021-00530-0 *

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