WO2017165956A1 - Analyse métabolomique de l'hypernéphrome - Google Patents

Analyse métabolomique de l'hypernéphrome Download PDF

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WO2017165956A1
WO2017165956A1 PCT/CA2017/000069 CA2017000069W WO2017165956A1 WO 2017165956 A1 WO2017165956 A1 WO 2017165956A1 CA 2017000069 W CA2017000069 W CA 2017000069W WO 2017165956 A1 WO2017165956 A1 WO 2017165956A1
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sample
metabolites
acid
aminoisobutyrate
rcc
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Hans J. Vogel
Eric HYNDMAN
Oluyemi FALEGAN
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Uti Limited Partnership
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    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5038—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving detection of metabolites per se
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/465—NMR spectroscopy applied to biological material, e.g. in vitro testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/4625—Processing of acquired signals, e.g. elimination of phase errors, baseline fitting, chemometric analysis

Definitions

  • Renal cell carcinoma accounts for 2-3% of all adult malignancies and is the most lethal of the genitourinary cancers.
  • Most renal masses are identified incidentally by ultrasound (US) or computed tomography (CT) imaging, which cannot distinguish RCC from benign renal lesions. Moreover, 20-30% of small incidental lesions that are surgically removed are found to be benign.
  • US ultrasound
  • CT computed tomography
  • 20-30% of small incidental lesions that are surgically removed are found to be benign.
  • ⁇ 4cm are low grade, noninvasive, and thought to be indolent. Therefore, many of these masses are surgically removed or ablated without significant benefit to patients. This confers increased morbidity and cost to the health care system that could be avoided if non- invasive accurate diagnosis of incidentally identified renal masses were possible.
  • Renal mass biopsy may be helpful but is prone to sampling error and ultimately is invasive and associated with some morbidity.
  • Mutations affecting hypoxia inducible factor (HIF), succinate dehydrogenase and fumarate hydratase are known to directly and indirectly alter cellular metabolism and contribute to cellular growth.
  • Targeted therapies with tyrosine kinase inhibitors have had some success in intervening in advanced disease. Nuclear magnetic resonance (NMR) spectroscopy and chromatography-coupled mass spectrometry (MS) methodologies in combination with multivariate statistical data analysis are currently the most widely employed metabolomics platforms for detecting and measuring metabolites.
  • NMR nuclear magnetic resonance
  • MS chromatography-coupled mass spectrometry
  • Gas chromatography involves the separation of volatile and semi- volatile compounds, which is then coupled to a mass spectrometer where the metabolites are ionized and resolved according to their mass/charge ratio.
  • Gas chromatography-mass spectrometry has a higher sensitivity than NMR but not all features detected can be classified as metabolites. The two techniques can provide complementary information. [11, 12]
  • the present invention provides various methods for characterization of the presence of or the severity of RCC disease in a subject.
  • the methods herein involve measurement of two or more metabolites that have been determined to be linked to the presence of RCC and/or the severity of the disease.
  • An increase in one or more metabolites in a selected sample or a decrease in one or more metabolites in a selected sample is herein linked to the presence and/or the severity of RCC.
  • Disease severity is for example assessed by determining the stage of RCC that exists in a given subject.
  • the methods herein can be employed to diagnose RCC and to stage RCC in a given patient.
  • the methods herein can be employed to monitor progress of RCC disease in a subject.
  • the methods herein can be employed to determine or at least assist in the determination of the type of treatment that is to be recommended for a given patient.
  • the methods herein can be employed to assess the effectiveness of treatment of RCC in a patient diagnosed to have the disease.
  • the methods herein can be employed to determine an RCC metabolic profile of a given test subject at a given time.
  • Such RCC metabolic profiles can be compared, either qualitatively or quantitatively, with metabolic profiles of appropriate control subjects to assess the presence of RCC, the severity or stage of RCC, to monitor RCC progress, to determine the type of treatment to recommend, and to assess the effectiveness of a given treatment.
  • MetaboUc profiles of an individual determined at different times can be compared to assess changes in disease state over time. Metabolic profiles of a test subject or various control metaboUc profiles are also generally useful in methods of research directed toward better understanding of the causes and mechanism(s) of RCC development and the development of new treatments of the disease.
  • the metaboUtes employed in the methods herein are those that are listed variously in Tables 1, 2, 3, 4 and 5 herein.
  • two or more, five or more, ten or more, fifteen or more twenty or more, twenty-five or more, thirty or more, forty or more or fifty or more metaboUtes are employed in establishing a metabolic profile.
  • various combinations of metabolites as detailed herein below are employed in establishing a metabolic profile.
  • Certain metaboUtes herein have been identified in serum samples and certain metaboUtes have been identified in urine samples. Most generally any combination of metaboUtes identified herein can be measured in any body fluid or body tissue to establish a metaboUc profile.
  • Certain metabolites have been identified using NMR methods.
  • Certain metabolites have been identified using GCMS methods.
  • Most generally any combination of metabolites identified herein can be measured in any body fluid or body tissue sample employing any known analytically method appropriate for the metabolite or sample to establish a metaboUc profile.
  • kits useful in one or more methods of the invention in which a qualitative or quantitative measurement of one or more of the identified metabolites is employed.
  • Kits of the invention include any combination of two or more different reference metabolites identified herein as associated with RCC as defined in Tables 1, 2, 3, 4 and 5 herein and in the examples herein.
  • a kit of the invention includes two or more, five or more, ten or more, fifteen or more twenty or more, twenty-five or more, thirty or more, forty or more or fifty or more metabolites identified herein.
  • the reference metabolites of the kit can be appropriately labeled and/or derivatized, for use with a given analytical technique.
  • reference metabolites may be isotopically labelled to facilitate mass spectral analysis.
  • kits may further include one or more chemical reagents, derivatizing agents, or other equipment, filters or containers to facilitate measurement of metabolites in a selected type of sample. Methods employing the kits herein for such measurements are provided in the invention.
  • FIGs. 1A-1B A characteristic 600 MHz ⁇ -NMR spectra of serum sample (FIG. 1A). A portion of the aliphatic region (3.0 - 4.0 ppm, expanded FIG. IB) and resonances from the most prevalent compounds are identified as follows: 1: 3-hydroxybutyrate, 2: lactate, 3: creatine, 4: serine, 5: glucose, 6: glycerol, 7: valine, 8: threonine, 9: glycine, 10: methanol, 11: choline, 12: acetylcarnithine, 13, 14, 15: lysine, ornithine, creatinine.
  • FIGs 3A-E GCMS orthogonal partial least squares discriminant analysis (OPLS-DA) models distinguishing between benign and cancer cases.
  • OPLS-DA score scatter plots showing separation in the serum metabolic profile of (FIG. 3A) stage 1 versus stage 3 cancer cases (FIG. 3B) benign versus stage 3 cancer cases (FIG. 3C) low grade (FuhrmanL - stages 1 &2) versus High grade (FuhrmanH -stages 3&4) cancer along their orthogonal partial least squares (OPLS 1) and partial least squares components (PLS1),
  • FIG. 3D OPLS-DA score scatter plots depicting the urine metabolic signature distinguishing benign subjects from stage 3 and (FIG. 3E) benign cases from high grade (FuhrmanH- stages 3&4).
  • FIGs. 4A and 4B are pairs (serum and urine) of ROC curves illustrating performance of the GCMS models in distinguishing between benign and stage 3 disease (FIG. 4A, serum and FIG. 4B, urine).
  • AUROC- area under the ROC curve TPF - true positive fraction (Sensitivity); FPF - false positive fraction (1 - Specificity).
  • FIGs 4C and 4D are ROC curve illustrating performance of the NMR models in distinguishing between benign and stage 3 disease (FIG. 4C, serum and FIG. 4D, urine).
  • AUROC- area under the ROC curve TPF - true positive fraction (Sensitivity); FPF - false positive fraction (1 - Specificity).
  • FIGs. 4E and 4F are ROC curves for the NMR models distinguishing between benign and stage 1 disease (FIG. 4E, serum and FIG. 4F. urine).
  • AUROC- area under the ROC curve TPF - true positive fraction (Sensitivity); FPF - false positive fraction (1 - Specificity).
  • NMR nuclear magnetic resonance
  • GCMS gas chromatography mass spectrometry
  • metabolites which when present in a sample of a body fluid or tissue of a subject, particularly in serum or urine of a subject, are linked to RCC in that subject.
  • the term metabolite refers generally to small molecules with molecular weight less than about 1000 daltons.
  • the term as used herein does not include nucleic acids or proteins or biological macromolecules, such as polysaccharides.
  • the term includes fatty acids and the carboxylate anions thereof. Certain acids are metabolites identified in Tables herein and are for the most part identified by the carboxylate anion of the acid, for example, lactate also refers to lactic acid.
  • metabolites and reference metabolites which are named as carboxylate anions can be provided variously as the carboxylic acid, or as an appropriate carboxylate salt.
  • Various metabolites are named in Tables 1-5 herein. It will be appreciated that a given chemical species can be named differently dependent upon the naming conventions that are employed.
  • Tables 1, 2 and 3 provide listing of metabolites in a body fluid linked to RCC.
  • Table 4 also provides certain fatty acids, the presence of which in a sample body fluid, particularly a serum sample, indicates the presence of RCC or the severity of the disease.
  • Table 5 provides differential metabolites linked to cancer which are designated significant metabolites having p ⁇ 0.05.
  • the metabolites listed in Table 5, which have certain overlap with those of Tables 1-3, are those preferred for use in assays herein. More specifically as noted in the Tables, increases in certain metabolites or decreases in certain other metabolites in a body fluid of a subject compared to the amount of such metabolites in appropriate healthy control subjects are linked to RCC.
  • an increase in certain metabolites or a decrease in certain metabolites in a test sample body fluid with respect to analogous samples from one or more healthy control subject, particularly serum or urine samples, is indicative of the presence of RCC.
  • An increase or decrease can be with respect to an appropriate control sample (e.g., a sample from a healthy subject), an increase or decrease for a given metabolite can be relative to one or more other metabolites in a sample or an increase or decrease may be with respect to a known amount of internal reference metabolite.
  • Such internal reference metabolite can be added to a test sample prior to measurement and the reference and its known amount are appropriate for a given measurement technique.
  • a decrease in a metabolite may be reflected in the absence of the metabolite (i.e., below detection limit) in a given test sample.
  • measurement includes qualitative measurement including the measurement of the presence or absence of one or more metabolites in or from a test sample.
  • Measurement also includes quantitative measurement of amounts of one or more metabolites with respect to reference known amounts of one or more metabolites. Amounts of a given metabolite may be assessed with respect to a known amount of added internal control, for example.
  • Measurement also includes relative quantitative measurement of relative amounts of two or more metabolites in a test sample. Relative quantitation may be compared to relative amounts in appropriate control samples, for example.
  • the invention relates to methods for diagnosis, monitoring the progression of, prognosis and/or treatment of RCC which rely upon the measurement of the presence, relative amount(s) or absolute amounts of two or more metabolites linked to RCC.
  • the methods herein employ measurement of three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-five or more, thirty or more, thirty-five or more, forty or more, or all of the metabolites listed in Tables 1, 2, or 3.
  • the methods herein employ measurement of two or more metabolites of Tables 1 , 2 or 3 which is increased in an RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample. In specific embodiments, the methods herein employ measurement of two or more metabolites of Tables 1, 2 or 3 which is decreased in a RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample. In specific embodiments, the methods herein employ measurement of one or more metabolites of Tables 1, 2 or 3 which is increased in an RCC body fluid sample and one or more metabolites of these Tables which is decreased in an RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample.
  • the methods herein employ measurement of two, three, four, five or more metabolites of Table 1, column A and/or two, three, four, five or more metabolites of Table 1, column B. In specific embodiments, the methods herein employ measurement of six, seven, eight, nine, ten or more metabolites of Table 1 , column A and/or one-ten or more metabolites of Table 1, column B. In specific embodiments, the methods herein employ measurement of one, two, three, four, five or more metabolites of Table 1 , column A and/or one-ten or more metabolites of Table 1, column B.
  • the methods herein employ measurement of one-ten or more metabolites of Table 1, column A and/or one, two, three, four, five or more metabolites of Table 1, column B. In specific embodiments, the methods herein employ measurement of one-ten or more metabolites of Table 1, column A and/or one-ten or more metabolites of Table 1, column B.
  • the metabolites of Table 1A which are measured are one, two, three, four, five, six, seven, eight, nine or ten of creatinine, eicosanoate, glycine, histidine, 3-aminosiobutyrate, 3- hydroxyisobutyrate, inositol, 5-methylcytosine, methylhistidine or 2-oxocitrate.
  • the metabolites of Table 1A which are measured are one, two, three, four, five, six, seven or eight, of creatinine, glycine, histidine, 3-aminosiobutyrate, 3 -hydroxyisobutyrate, inositol, 5-methylcytosine, or 2-oxocitrate.
  • the metabolites of Table 1 A which are measured are one, two, three, four, five, or six of creatinine, glycine, histidine, 3- aminosiobutyrate, 3-hydroxyisobutyrate, or inositol.
  • the metabolites of Table IB which are measured are one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen of acetate, 2-aminoisobutyrate, betaine, dimethylamine, glutamine, methanol, octadecanoate, ornithine, oxypurinol, taurine, thymine, trigonelline, tryptophan, gluconate, or glucose.
  • the methods herein employ measurement of one or more fatty acids as listed in Table 4 alone or in combination with measurement of one or more metabolites of any one or more of Tables 1 , 2 or 3.
  • the methods herein employ measurement of three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-five or more, thirty or more, thirty-five or more, forty or more, or all of the metabolites listed in Table 5.
  • the methods herein employ measurement of two or more metabolites of Table 5 which is increased in an RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample.
  • the methods herein employ measurement of two or more metabolites of Table 5 which is decreased in a RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample.
  • the methods herein employ measurement of one or more metabolites of Table 5 which is increased in an RCC body fluid sample and one or more metabolites of Table 5 which is decreased in an RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample.
  • the methods herein employ measurement of succinate and/or citrate which is decreased in a RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample. In specific embodiments, the methods herein employ measurement of pyruvate and/or lactate which is decreased in a RCC body fluid sample compared to the metabolite(s) in an appropriate control body fluid control sample.
  • measurement of one or more of creatinine, eicosanoate, glycine, histidine, 3- hydroxyisobutyrate, 3-aminosiobutyrate, inositol, 5-methylcytosine, methylhistidine or 2- oxocitrate is combined with measurement of one or more of pyruvate, lactate, succinate or citrate.
  • measurement of one or more of acetate, 2-aminoisobutyrate, betaine, dimethylamine, glutamine, methanol, octadecanoate, ornithine, oxypurinol, taurine, thymine, trigonelline, tryptophan, gluconate, or glucose is combined with measurement of one or more of pyruvate, lactate, succinate or citrate.
  • measurement of one or more of creatinine, eicosanoate, glycine, histidine, 3-aminosiobutyrate, 3-hydroxyisobutyrate, inositol, 5- methylcytosine, methylhistidine or 2-oxocitrate is combined with measurement of pyruvate or lactate and succinate or citrate.
  • measurement of one or more of acetate, 2- aminoisobutyrate, betaine, dimethylamine, glutamine, methanol, octadecanoate, ornithine, oxypurinol, taurine, thymine, trigonelline, tryptophan, or gluconate is combined with measurement of pyruvate or lactate and succinate or citrate.
  • measurement of one, two, three, four, five, six, seven, eight, nine or ten of creatinine, eicosanoate, glycine, histidine, 3-aminosiobutyrate, 3-hydroxyisobutyrate, inositol, 5- methylcytosine, methylhistidine or 2-oxocitrate is combined with measurement of one, two, three or four of pyruvate, lactate, succinate or citrate.
  • measurement of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen of acetate, 2-aminoisobutyrate, betaine, dimethylamine, glutamine, methanol, octadecanoate, ornithine, oxypurinol, taurine, thymine, trigonelline, tryptophan or gluconate is combined with measurement of one, two, three or four of pyruvate, lactate, succinate or citrate.
  • measurements are conducted employing any known analytical technique for measurement of a given metabolite in a given body fluid.
  • Body fluids include among others plasma, serum, urine, semen, and saliva.
  • preferred samples are serum and urine samples.
  • measurements herein are not conducted with tumor tissue or fluid obtained from tumor tissue.
  • urine samples are measured for one, two, three, four, five, six, seven, eight, nine, ten or more metabolites of Table 2, column UA. In specific embodiments, urine samples are measured for one, two, three, four, five, six, seven, eight, nine, ten or more metabolites of Table 2, column UB. In specific embodiments, urine samples are measured for one, two, three, four, five, six, seven, eight, nine, ten or more metabolites of Table 2, column UA and one, two, three, four, five, six, seven, eight, nine, ten or more metabolites of column UB.
  • urine samples are measured for one or more metabolites selected from creatinine, erythritol, fucose, glycine, 3-hydoxyisobutyrate, inositol, mannitol, methylhistidine or phenylalanine.
  • urine samples are measured for one or more metabolites selected from creatinine, 3- hydoxyisobutyrate, inositol, or methylhistidine.
  • urine samples are measured for one or more metabolites selected from acetate, 2- aminoisobutyrate, betaine, dimethylamine, oxypurinol, thymine, trigonelline, tryptophan, gluconate or glucose.
  • urine samples are measured for one or more metabolites selected from creatinine, erythritol, fucose, glycine, 3- hydoxyisobutyrate, inositol, mannitol, methylhistidine or phenylalanine and one or more metabolites selected from acetate, 2-aminoisobutyrate, betaine, dimethylamine, oxypurinol, thymine, trigonelline, tryptophan, gluconate or glucose.
  • urine samples are measured for one or more metabolites selected from creatinine, 3- hydoxyisobutyrate, inositol, or methylhistidine and one or more metabolites selected from acetate, 2-aminoisobutyrate, betaine, dimethylamine, oxypurinol, thymine, trigonelline, tryptophan, gluconate or glucose.
  • urine samples are measured using ⁇ -NMR methods.
  • urine samples are measured using GCMS methods.
  • serum samples are measured for one, two, three, four, five, six, or seven, metabolites of Table 2, column SA. In specific embodiments, serum samples are measured for one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve metabolites of Table 2, column UB. In specific embodiments, serum samples are measured for one, two, three, four, five, six, or seven, metabolites of Table 2, column UA and one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve metabolites of column UB.
  • serum samples are measured for one or more metabolites selected from creatinine, 2-oxoisocitrate, theophylline, glycine, histidine, 5-methylcytosine or eicosanoate.
  • serum samples are measured for one or more metabolites selected from creatinine, 2-oxoisocitrate, histidine, 5-methlcytosine or eicosanoate.
  • serum samples are measured for one or more metabolites selected from glutamate, glutamine, methanol, octadecanoate, ornithine, taurine or threonine.
  • serum samples are measured for one or more metabolites selected from methanol, octadecanoate, ornithine, taurine or threonine.
  • serum samples are measured for one or more metabolites selected from creatinine, 2-oxoisocitrate, theophylline, glycine, histidine, 5-methylcytosine or eicosanoate and one or more metabolites of Table 2, column SB.
  • serum samples are measured for one or more metabolites selected from creatinine, 2-oxoisocitrate, histidine, 5-methlcytosine or eicosanoate and one or more metabolites of Table 2, column SB.
  • serum samples are measured for one or more metabolites selected from glutamate, glutamine, methanol, octadecanoate, ornithine, taurine or threonine and one or more metabolites of Table 2, column SA.
  • serum samples are measured for one or more metabolites selected from methanol, octadecanoate, ornithine, taurine or threonine and one or more metabolites of Table 2, column SA.
  • serum samples are measured using ⁇ -NMR methods.
  • urine samples are measured using GCMS methods.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven or eight metabolites selected from citrate, succinate, glycine, 3-aminosiobutyrate, 3-hydroxyisobutyrate, phenylalanine, creatinine, or methylhistidine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four or five metabolites selected from glycine, 3- aminosiobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine.
  • the methods herein employ : H-NMR measurement of urine samples of one, two, three or four metabolites selected from 3-aminosiobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine.
  • herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven, eight, nine, ten or eleven metabolites selected from pyruvate, lactate, oxypurinol, gluconate, malonate, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven, or eight metabolites selected from oxypurinol, gluconate, malonate, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • herein employ ⁇ -NMR measurement of urine samples of one, two, three, four, five, six or seven metabolites selected from oxypurinol, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • herein employ 'H-NMR measurement of urine samples of one, two, three, four or five metabolites selected from oxypurinol, 2-aminosiobutyrate, betaine, theophylline, or trigonelline.
  • the methods herein employ 'H-NMR measurement of urine samples of one, two, three, four, five, six, seven or eight metabolites selected from citrate, succinate, glycine, 3-aminosiobutyrate, 3-hydroxyisobutyrate, phenylalanine, creatinine, or methylhistidine and one, two, three, four, five, six, seven, eight, nine, ten or eleven metabolites selected from pyruvate, lactate, oxypurinol, gluconate, malonate, 2-aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four or five metabolites selected from glycine, 3-aminosiobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six, seven, eight, nine, ten or eleven metabolites selected from pyruvate, lactate, oxypurinol, gluconate, malonate, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three or four metabolites selected from 3- aminosiobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six, seven, eight, nine, ten or eleven metabolites selected from pyruvate, lactate, oxypurinol, gluconate, malonate, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ ⁇ -NMR measurement of urine samples of 3-aminosiobutyrate, 3-hydroxyisobutyrate, and 2- aminoisobutyrate.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven or eight metabolites selected from citrate, succinate, glycine, 3-aminoisobutyrate, 3-hydroxyisobutyrate, phenylalanine, creatinine, or methylhistidine and one, two, three, four, five, six, seven, eight or nine metabolites selected from oxypurinol, gluconate, malonate, 2-aminoisobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four or five metabolites selected from glycine, 3- aminoisobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six, seven, eight or nine metabolites selected from oxypurinol, gluconate, malonate, 2- aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ ⁇ -NMR measurement of urine samples of one, two, three or four metabolites selected from 3-aminoisobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six, seven, eight or nine metabolites selected from oxypurinol, gluconate, malonate, 2-aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven or eight metabolites selected from citrate, succinate, glycine, 3-aminoisobutyrate, 3-hydroxyisobutyrate, phenylalanine, creatinine, or methylhistidine and one, two, three, four, five, six or seven metabolites selected from oxypurinol, 2- aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ ⁇ -NMR measurement of urine samples of one, two, three, four or five metabolites selected from glycine, 3-aminoisobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six or seven metabolites selected from oxypurinol, 2-aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 'H-NMR measurement of urine samples of one, two, three or four metabolites selected from 3-aminoisobutyrate, 3- hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four, five, six or seven metabolites selected from oxypurinol, 2-aminosiobutyrate, betaine, theophylline, tryptophan, trigonelline, or dimethyamine.
  • the methods herein employ 1 H-NMR measurement of urine samples of one, two, three, four, five, six, seven or eight metabolites selected from citrate, succinate, glycine, 3-aminoisobutyrate, 3-hydroxyisobutyrate, phenylalanine, creatinine, or methylhistidine and one, two, three, four, or five metabolites selected from oxypurinol, 2-aminosiobutyrate, betaine, trigonelline, or dimethyamine.
  • the methods herein employ !
  • the methods herein employ ⁇ -NMR measurement of urine samples of one, two, three or four metabolites selected from 3- aminoisobutyrate, 3-hydroxyisobutyrate, creatinine or methylhistidine and one, two, three, four or five metabolites selected from oxypurinol, 2-aminosiobutyrate, betaine, trigonelline, or dimethyamine.
  • the methods herein use GCMS measurement in urine samples of one, two, three, four, five or six metabolites selected from erythritol, 2-oxoglutarate, inositol, mannitol or fucose. In specific embodiments, the methods herein use GCMS measurement in urine samples of one, two, three, or four metabolites selected from erythritol, 2-oxoglutarate, inositol, or mannitol. In specific embodiments, the methods herein use GCMS measurement in urine samples of one, two or three metabolites selected from erythritol, 2-oxoglutarate or inositol. In specific embodiments, the methods herein use GCMS measurement in urine samples of one, two, or three metabolites selected from acetate, gluconate or thymine.
  • the methods herein use GCMS measurement in urine samples of one, two, three, four, five or six metabolites selected from erythritol, 2-oxoglutarate, inositol, mannitol or fucose and one, two, or three metabolites selected from acetate, gluconate or thymine.
  • the methods herein use GCMS measurement in urine samples of one, two, three, or four metabolites selected from erythritol, 2-oxoglutarate, inositol, or mannitol and one, two, or three metabolites selected from acetate, gluconate or thymine.
  • the methods herein use GCMS measurement in urine samples of one, or two metabolites selected from erythritol, or inositol and one, two, or three metabolites selected from acetate, gluconate or thymine.
  • the methods herein use GCMS measurement in urine samples of one, two or three metabolites selected from erythritol, 2- oxoglutarate or inositol and one, two, or three metabolites selected from acetate, gluconate or thymine.
  • Various methods for performing GCMS analysis are known in the art and all such known methods appropriate for analysis of serum samples can be employed for measurement in the methods herein.
  • the methods herein employ 1 H-NMR measurement of serum samples of one, two, three, four, or five metabolites selected from creatine, 2-oxoisocitrate, theophylline, glycine or histidine.
  • the methods herein employ 'H-NMR measurement of serum samples of one, two or three metabolites selected from creatine, 2- oxoisocitrate, or histidine.
  • the methods herein employ ⁇ -NMR measurement of serum samples of one, two, three, four, five, six, seven or eight of taurine, methanol, threonine, glutamine, citrate, ornithine, glutamate, or isoleucine.
  • the methods herein employ ⁇ -NMR measurement of serum samples of one, two, three, four, or five, of taurine, methanol, threonine, ornithine, or isoleucine. In specific embodiments, the methods herein employ 'H-NMR measurement of serum samples of one, two, or three of taurine, threonine, or ornithine.
  • the methods herein employ 1 H-NMR measurement of serum samples of one, two, three, four, or five metabolites selected from creatine, 2-oxoisocitrate, theophylline, glycine or histidine and one, two, three, four, five, six, seven or eight of taurine, methanol, threonine, glutamine, citrate, ornithine, glutamate, or isoleucine.
  • the methods herein employ : H-NMR measurement of serum samples of one, two, three, four, or five metabolites selected from creatine, 2- oxoisocitrate, theophylline, glycine or histidine and one, two, three, four, or five, of taurine, methanol, threonine, ornithine, or isoleucine.
  • the methods herein employ 'H-NMR measurement of serum samples of one, two, three, four, or five metabolites selected from creatine, 2-oxoisocitrate, theophylline, glycine or histidine and one, two, or three of taurine, threonine, or ornithine.
  • the methods herein employ ⁇ - NMR measurement of serum samples of one, two or three metabolites selected from creatine, 2- oxoisocitrate, or histidine and one, two, three, four, five, six, seven or eight of taurine, methanol, threonine, glutamine, citrate, ornithine, glutamate, or isoleucine.
  • the methods herein employ 1 H-NMR measurement of serum samples of one, two or three metabolites selected from creatine, 2-oxoisocitrate, or histidine and one, two, three, four, or five, of taurine, methanol, threonine, ornithine, or isoleucine.
  • the methods herein employ ⁇ -NMR measurement of serum samples of one, two or three metabolites selected from creatine, 2-oxoisocitrate, or histidine and one, two, three, four, or five, of taurine, methanol, threonine, ornithine, or isoleucine.
  • the methods herein employ ⁇ -NMR measurement of serum samples of one, two or three metabolites selected from creatine, 2-oxoisocitrate, or histidine and one, two, or three of taurine, threonine, or ornithine.
  • the methods herein use GCMS measurement in serum samples of 5- methylcytosine or eicosanoate. In specific embodiments, the methods herein use GCMS measurements in serum samples of one, two, three, four, five or six metabolites selected from glutamate, lactate, citrate, octadecanoate, galactose, or pyruvate. In specific embodiments, the methods herein use GCMS measurements in serum samples of one, two, or three metabolites selected from glutamate, octadecanoate, or galactose.
  • the methods herein use GCMS measurement in serum samples of 5-methylcytosine or eicosanoate and one, two, three, four, five or six metabolites selected from glutamate, lactate, citrate, octadecanoate, galacose, or pyruvate.
  • the methods herein use GCMS measurement in serum samples of 5-methylcytosine or eicosanoate and one, two, or three metabolites selected from glutamate, octadecanoate, or galactose.
  • Various methods for performing GCMS analysis are known in the art and all such known methods appropriate for analysis of serum samples can be employed for measurement in the methods herein.
  • the metabolites are measured in a serum or a urine sample. In specific embodiments measurements are made on serum samples and urine samples. In specific embodiments, the metabolites are measured by NMR or GCMS methods. In specific embodiments, the metabolites are measured in a serum or a urine sample. In specific embodiments, the metabolites are measured by ⁇ NMR or GCMS methods.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, eight or more of, nine or more of, ten or more of, fifteen or more of, or all of 2-aminoisobutyrate, 5-methylcytosine, citrate, eicosanoate, erythritol, galactose, glucose, glutamate, glycine, histidine, hypoxanthine, isoleucine, lactate, methylhistidine, myoinositol, ornithine, 2-oxoglutarate, phenylalanine, pyruvate, or succinate are measured in a sample.
  • the metabolites are measured in a serum or a urine sample.
  • measurements are made on serum samples and urine samples.
  • the metabolites are measured by NMR or GCMS methods.
  • the metabolites are measured in a serum or a urine sample.
  • the metabolites are measured by 'HNMR or GCMS methods.
  • two or more of, three or more of, four or more of, or all of succinate, 2- aminoisobutyrate, glutamate, glucose, or eicosanoate are measured in a sample.
  • the metabolites are measured in a serum or a urine sample.
  • measurements are made on serum samples and urine samples.
  • the metabolites are measured by NMR or GCMS methods.
  • the metabolites are measured in a serum or a urine sample.
  • the metabolites are measured by 'HNMR or GCMS methods.
  • methylhistidine, or phenylalanine are measured in a sample.
  • the metabolites are measured in a serum or a urine sample. In specific embodiments measurements are made on serum samples and urine samples.
  • the metabolites are measured by NMR or GCMS methods. In specific embodiments, the metabolites are measured in a serum or a urine sample. In specific embodiments, the metabolites are measured by 'HNMR or GCMS methods.
  • pyruvate or lactate is measured in a serum sample by GCMS methods and one or more of succinate, 2-aminoisobutyrate, glutamate, glucose, eicosanoate,
  • methylhistidine, or phenylalanine are measured in a sample.
  • the additional one or more metabolites are measured in a serum or a urine sample.
  • measurements of the additional one or more metabolites are made on serum samples and urine samples.
  • the one or more additional metabolites are measured by NMR or GCMS methods.
  • the additional one or more metabolites are measured by ⁇ NMR or GCMS methods.
  • pyruvate or lactate is measured in a urine sample by NMR methods, particularly by ⁇ NMR methods, and one or more of succinate, 2-aminoisobutyrate, glutamate, glucose, eicosanoate, methylhistidine, or phenylalanine are measured in a sample.
  • the additional one or more metabolites are measured in a serum or a urine sample.
  • measurements of the additional one or more metabolites are made on serum samples and urine samples.
  • the one or more additional metabohtes are measured by NMR or GCMS methods.
  • the additional one or more metabohtes are measured by 'HNMR or GCMS methods.
  • one or more of succinate, 2-aminoisobutyrate, glutamate, glucose, eicosanoate, methylhistidine, or phenylalanine; one or more of citrate, 5-methylcytosine, glycine, isoleucine, ornithine, galactose, 2-oxoglutarate, or myo-inositol is measured in a sample.
  • the metabohtes are measured in a serum or a urine sample.
  • measurements are made on serum samples and urine samples.
  • the metabolites are measured by NMR or GCMS methods.
  • the metabohtes are measured in a serum or a urine sample.
  • the metabohtes are measured by 'HNMR or GCMS methods.
  • one or more of succinate, 2-aminoisobutyrate, glutamate, glucose, eicosanoate, methylhistidine, or phenylalanine; one or more of citrate, 5-methylcytosine, glycine, isoleucine, ornithine, galactose, 2-oxoglutarate, or myo-inositol and one or both of pyruvate and lactate is measured in a sample.
  • the metabohtes are measured in a serum or a urine sample. In specific embodiments measurements are made on serum samples and urine samples.
  • the metabolites are measured by NMR or GCMS methods. In specific embodiments, the metabohtes are measured in a serum or a urine sample. In specific embodiments, the metabolites are measured by 'HNMR or GCMS methods.
  • eicosanoate and glutamate are measured in a serum sample. In specific embodiments, two or more of or three or more of eicosanoate, glutamate, pyruvate or lactate are measured in a serum sample. In specific embodiments, eicosanoate, glutamate, pyruvate and lactate are all measured in a serum sample.
  • eicosanoate and glutamate are measured along with one or more of citrate, creatine, galactose, glutamine, glycine, histidine, isoleucine, lactate, methanol, 5- methylcytosine, octadecanoate, ornithine, 2-oxoisocaproate, pyruvate, taurine, threonine, or tyrosine are measured in a serum sample.
  • eicosanoate, glutamate, pyruvate and lactate along with one or more of citrate, creatine, galactose, glutamine, glycine, histidine, isoleucine, methanol, 5-methylcytosine, octadecanoate, ornithine, 2-oxoisocaproate, taurine, threonine, or tyrosine are measured in a serum sample.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, or all eight of 5-methylcytosine, eicosanoate, isoleucine, glutamate, ornithine, galactose, pyruvate or lactate is measured in a serum sample.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, eight or more of, nine or more of, ten or more of or all of citrate, creatine, glutamine, glutamate, glycine, histidine, isoleucine, methanol, ornithine, 2- oxoisocaproate, taurine, or threonine is measured in a serum sample.
  • the above listed serum metabolites are measured by 1H NMR.
  • isoleucine, glutamate and ornithine are measured in a serum sample by ⁇ NMR.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, or all of eicosanoate, galactose, glutamate, lactate, 5- methylcytosine, octadecanoate, pyruvate, or tyrosine are measured in a serum sample.
  • the above listed serum metabolites are measured by GCMS.
  • eicosanoate, 5-methylcytosine, galactose, pyruvate and lactate are measured in a serum sample by GCMS.
  • eicosanoate and glutamate are measured in a serum sample. In specific embodiments, two or more of or three or more of eicosanoate, glutamate, pyruvate or lactate are measured in a serum sample. In specific embodiments, eicosanoate, glutamate, pyruvate and lactate are all measured in a serum sample.
  • eicosanoate and glutamate are measured along with one or more of citrate, creatine, galactose, glutamine, glycine, histidine, isoleucine, lactate, methanol, 5- methylcytosine, octadecanoate, ornithine, 2-oxoisocaproate, pyruvate, taurine, threonine, or tyrosine are measured in a serum sample.
  • eicosanoate, glutamate, pyruvate and lactate along with one or more of citrate, creatine, galactose, glutamine, glycine, histidine, isoleucine, methanol, 5-methylcytosine, octadecanoate, ornithine, 2-oxoisocaproate, taurine, threonine, or tyrosine are measured in a serum sample.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, or all eight of 5-methylcytosine, eicosanoate, isoleucine, glutamate, ornithine, galactose, pyruvate or lactate is measured in a serum sample.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, eight or more of, nine or more of, ten or more of or all of citrate, creatine, glutamine, glutamate, glycine, histidine, isoleucine, methanol, ornithine, 2- oxoisocaproate, taurine, or threonine is measured in a serum sample.
  • the above listed serum metabolites are measured by l H NMR.
  • isoleucine, glutamate and ornithine are measured in a serum sample by ⁇ NMR.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, or all of eicosanoate, galactose, glutamate, lactate, 5- methylcytosine, octadecanoate, pyruvate, or tyrosine are measured in a serum sample.
  • the above listed serum metabolites are measured by GCMS.
  • eicosanoate, 5-methylcytosine, galactose, pyruvate and lactate are measured in a serum sample by GCMS.
  • three or more or all of glucose, erythritol, 2-oxoglutarate, and myoinositol are measured in a urine sample.
  • pyruvate and lactate are measured in a urine sample by ⁇ NMR.
  • citrate, succinate, glycine, 2-aminoisobutyrate, phenylalanine, and methyl histidine are measured in a urine sample by ⁇ NMR.
  • pyruvate, lactate, citrate, succinate, glycine, 2-aminoisobutyrate, phenylalanine, and methyl histidine are measured in a urine sample by ⁇ NMR.
  • 2-aminoisobutyrate, succinate, and methyl histidine are measured in a urine sample by ⁇ NMR.
  • 2- aminoisobutyrate, succinate, phenylalanine and methyl histidine are measured in a urine sample by ⁇ NMR.
  • pyruvate and lactate are measured along with one or more of citrate, succinate, glycine, 3-hydroxybutyrate, creatinine, 2-aminoisobutryate, phenylalanine, methylhistidine, oxypurinol, gluconate, hypoxanthine, malonate, betaine, tryptophan, trigonelline, or dimethylamine, in a urine sample by ! H NMR.
  • two or more of, three or more of, four or more of, five or more of, six or more of, seven or more of, eight or more of, nine or more of, ten or more of, fifteen or more of twenty or more of, twenty- five or more of, or all of citrate, succinate, glycine, 3- hydroxybutyrate, creatinine, 2-aminoiosbutryate, phenylalanine, methylhistidine, pyruvate, lactate, oxypurinol, gluconate, hypoxanthne, malonate, betaine, tryptophan, trigonelline, or dimethylamine are measured in a urine sample.
  • the above listed urine metabolites are measured by 'H-NMR.
  • one or more of glucose, erythritol, 2-oxoglutarate, or myo-inositol and one or more of acetate, threonine, gluconate, thymine, mannitol, or citrate are measured in a urine sample by GCMS methods.
  • two or more of glucose, erythritol, 2-oxoglutarate, or myo-inositol and two or more of acetate, threonine, gluconate, thymine, mannitol, or citrate are measured in a urine sample by GCMS methods.
  • glucose, erythritol, 2-oxoglutarate, and myo-inositol and one or more of acetate, threonine, gluconate, thymine, mannitol, or citrate are measured in a urine sample by GCMS methods.
  • the present invention relates at least in part to measuring a metabolite profile of a subject with respect to RCC.
  • the metabolite profile involves measurement of the presence or absence, relative amount, or absolute amount of two or more metabolites as identified herein as linked to RCC.
  • a subject alternatively an individual, is any animal.
  • a subject can be a mammal.
  • a subject can be a human.
  • a subject may be a patient who is seeking diagnosis for RCC or has been diagnosed as having RCC and is being treated or considering treatment options for the disease.
  • Metabolite profiles can be obtained for test subjects using methods described herein.
  • AUC the area under the curve (AUC)
  • TCA tricarboxylic acid cycle
  • ROC curves were constructed for all GCMS and NMR models using SIMCA P+ (FIGs. 4A-4F) except the pTl versus pT3 GCMS model which comprised of two diseased groups.
  • the serum and urine GCMS models had AUC values of 0.9293 and 0.9820 respectively and AUC values for NMR models ranged from 0.8268 to 0.9767.
  • Neoplastic cells satisfy their high metabolic needs through mechanisms that include fatty acid biosynthesis and other non-glycolytic metabolism. [19] These cells acquire most of their fatty acid quota from de novo synthesis and hence, altered lipogenesis is a characteristic of cancer.
  • AUC values calculated in this study exceeded 0.8, this indicates excellent predictive ability of these metabolomic platforms and shows that they can reliably distinguish between benign and malignant renal masses and identify different stages of RCC.
  • the AUC values computed for the GCMS analysis are considerably higher than the NMR values; which may be as a result of the higher sensitivity associated with GCMS.
  • the urine samples also seem to be better predictors of RCC stages than serum samples.
  • fatty acid assessment of RCC samples also provided insight into the influence of lipid metabolites on the disease.
  • OPLS-DA supervised orthogonal partial least squares-discriminant analysis
  • R2Y and Q2 metrics which describe the explained variation within the data set and the predictability of the model, respectively, were calculated based on the averages of the sevenfold cross-validation.
  • R2Y and Q2 values range between 0-1, and the closer these metrics are to 1, the higher the variance explained by the model and the more reliable the predictive power of the model.
  • PLS- DA models were built for each comparison and were found to have metrics similar to their OPLS-DA counterparts. The problem of OPLS-DA analysis being prone to overfitting is therefore ruled out in this dataset.
  • VIP Variable Influence on Projection
  • NMR and GCMS coupled with multivariate statistical analysis can distinguish between malignant and benign renal masses with up to 98% specificity and sensitivity. It was also found that integrating NMR and GCMS datasets revealed better discriminatory power and higher predictive ability.
  • GCS 0.032 metabolites Thymine Galatose Myo-inositol
  • Kaelin WG, Jr. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing.

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Abstract

L'invention concerne des méthodes de caractérisation de la présence d'un hypernéphrome ou de sa gravité chez un sujet, qui consiste à mesurer au moins deux métabolites déterminés comme étant associés à la présence d'hypernéphrome et/ou à la gravité de la maladie. Une augmentation ou une diminution d'un ou de plusieurs métabolites dans un échantillon sélectionné est associée à la présence d'hypernéphrome et/ou à sa gravité. Des méthodes peuvent être utilisées pour déterminer un profil métabolique d'un hypernéphrome chez un sujet donné à un moment donné. De tels profils et méthodes peuvent être utilisés pour diagnostiquer un hypernéphrome ou en déterminer les stades, et pour surveiller l'évolution d'un hypernéphrome chez un patient donné. De tels profils et méthodes peuvent être utilisés pour déterminer ou au moins aider à déterminer le type de traitement à recommander pour un patient donné et pour évaluer l'efficacité d'un traitement de l'hypernéphrome chez un patient. Une combinaison quelconque de métabolites identifiés par les méthodes de l'invention peut être mesurée dans n'importe quel échantillon de fluide corporel ou de tissu corporel, par n'importe quelle méthode analytique connue appropriée pour établir un profil métabolique à partir du métabolite ou de l'échantillon. L'invention concerne également des Kits utiles pour mettre en oeuvre de telles méthodes.
PCT/CA2017/000069 2016-03-28 2017-03-28 Analyse métabolomique de l'hypernéphrome WO2017165956A1 (fr)

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US11840720B2 (en) 2019-12-23 2023-12-12 Metabolomic Technologies Inc. Urinary metabolomic biomarkers for detecting colorectal cancer and polyps
WO2022023757A1 (fr) * 2020-07-29 2022-02-03 Oxford University Innovation Limited Diagnostic du cancer
WO2022054183A1 (fr) * 2020-09-09 2022-03-17 株式会社日立ハイテク Méthode de test du cancer utilisant une liste de métabolites
RU2805811C1 (ru) * 2022-06-09 2023-10-24 Федеральное государственное бюджетное учреждение науки Институт теоретической и экспериментальной биофизики Российской академии наук (ИТЭБ РАН) Способ диагностики почечно-клеточной карциномы по наличию зрительных белков аррестина и рековерина в моче

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