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WO1999060160A1 - Technique de diagnostic, de suivi et de stadification du cancer du poumon - Google Patents

Technique de diagnostic, de suivi et de stadification du cancer du poumon Download PDF

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Publication number
WO1999060160A1
WO1999060160A1 PCT/US1999/010344 US9910344W WO9960160A1 WO 1999060160 A1 WO1999060160 A1 WO 1999060160A1 US 9910344 W US9910344 W US 9910344W WO 9960160 A1 WO9960160 A1 WO 9960160A1
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WIPO (PCT)
Prior art keywords
lsg
levels
cancer
patient
tissue
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PCT/US1999/010344
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English (en)
Inventor
Fei Yang
Roberto A. Macina
Yongming Sun
Original Assignee
Diadexus Llc
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Publication date
Application filed by Diadexus Llc filed Critical Diadexus Llc
Priority to US09/700,770 priority Critical patent/US7160679B1/en
Priority to CA002328138A priority patent/CA2328138A1/fr
Priority to JP2000549766A priority patent/JP3688585B2/ja
Priority to EP99921894A priority patent/EP1082459A4/fr
Publication of WO1999060160A1 publication Critical patent/WO1999060160A1/fr

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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
    • G01N33/50—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
    • G01N33/57423—Specifically defined cancers of lung
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification

Definitions

  • This invention relates, in part, to newly developed assays for detecting, diagnosing, monitoring, staging, . and prognosticating cancers, particularly lung cancer.
  • Primary lung cancer is divided into three main types including small cell lung cancer, non-small cell lung cancer, and mesothelioma.
  • Small cell lung cancer is also called "Oat Cell” lung cancer because the cancer cells are a distinctive oat shape.
  • There are three types of non-small cell lung cancer which are grouped together based upon similar behavior patterns and response to treatment which is different from small cell lung cancer.
  • the three types of non-small cell lung cancer are squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Squamous cell cancer is the most common type of lung cancer. It develops from the cells that line the airways.
  • Adenocarcinoma also develops from the cells that line the airways, but it develops from a particular type of cell that produces mucus (phlegm) .
  • the cells appear large and rounded when viewed under a microscope.
  • Mesothelioma is a rare type of cancer which affects the covering of the lung, the pleura. It is often caused by exposure to asbestos.
  • Secondary lung cancer is cancer that has started somewhere else in the body (for example, the breast or bowel) and spread to the lungs.
  • the choice of treatment depends on where the cancer began. For example, cancer that has spread from the breast should respond to breast cancer treatments and cancer that has spread from the bowel should respond to bowel cancer treatments.
  • the stage of a cancer provides information regarding how far a cancer has spread. Staging is important because treatment of the cancer is often decided based upon its stage. Staging is different for non-small cell versus small cell cancers of the lung.
  • Non-small cell cancer is divided into four stages. Stage I is very localized cancer with no cancer in the lymph nodes. In stage II, cancer has spread to the lymph nodes at the top of the affected lung. In stage III, cancer has spread near to where the cancer started. This can be to the chest wall, the covering of the lung (pleura), the middle of the chest (mediastinum) or other lymph nodes. Stage IV cancer has spread to another part of the body.
  • Small cell lung cancers are divided into two groups. This is because small cell lung cancer often spreads quite early. Even if spreading of the cancer is not visible on scans, it is likely that some cancer cells will have broken away and traveled through the bloodstream or lymph system. Accordingly, it is often preferred to treat small cell lung cancers as if they have spread, whether or not any secondary cancer is seen.
  • the two stages of small cell lung cancers are limited disease, that is cancer that can only be seen in one lung and in nearby lymph nodes, and extensive disease, that is cancer that has spread outside the lung to the chest or to other parts of the body. Because surgery is not usually used to treat small cell cancer, except in very early cases, the staging is not as important as it is with some other types of cancer. Chemotherapy with or without radiotherapy is usually preferred for treatment of small cell lung cancers. Initial scans and tests are used for comparison with later scans and test to see how well a patient is responding to treatment.
  • Procedures used for detecting, diagnosing, monitoring, staging and prognosticating lung cancer are of critical importance to the outcome of the patient. For example, patients diagnosed with early lung cancer generally have a much greater five-year survival rate as compared to the survival rate for patients diagnosed with distant metastasized lung cancer. New diagnostic methods which are more sensitive and specific for detecting early lung cancer are clearly needed.
  • Lung cancer patients are also closely monitored following initial therapy and during adjuvant therapy to determine response to therapy and to detect persistent or recurrent disease of metastasis.
  • a lung cancer marker which is more sensitive and specific in detecting lung cancer recurrence.
  • Stage determination has potential prognostic value and provides criteria for designing optimal therapy.
  • pathological staging of lung cancer is preferable over clinical staging because the former gives a more accurate prognosis.
  • clinical staging would be preferred were it at least as accurate as pathological staging because it does not depend on an invasive procedure to obtain tissue for pathological evaluation. Staging of lung cancer would be improved by detecting new markers in cells, tissues or bodily fluids which could differentiate between different stages of invasion.
  • LSGs Lung Specific Genes
  • the six LSGs refer, among other things, to native proteins expressed by the genes comprising the polynucleotide sequences of any of SEQ ID NO: 1, 2, 3, 4, 5 or 6.
  • the six LSGs as used herein means the native mRNAs encoded by the genes comprising any of the polynucleotide sequences of SEQ ID NO: 1, 2, 3, 4, 5 or 6 or levels of the genes comprising any of the polynucleotide sequences of SEQ ID NO: 1, 2, 3, 4, 5 or 6.
  • Another object of the present invention is to provide a method of diagnosing metastatic lung cancer in a patient which comprises measuring LSG levels in a sample of cells, tissue, or bodily fluid from the patient and comparing the measured LSG levels with levels of LSG in preferably the same cells, tissue, or bodily fluid type of a control, wherein an increase in measured LSG levels in the patient versus levels of LSG in the control is associated with a cancer which has metastasized.
  • Another object of the present invention is to provide a method of staging lung cancer in a patient which comprises identifying a patient having lung cancer, measuring levels of LSG m a sample of cells, tissues, or bodily fluid obtained from the patient, and comparing the measured LSG levels with levels of LSG in preferably the same cells, tissue or bodily fluid type of a control.
  • An increase m measured LSG levels in the patient versus LSG levels in the control can be associated with a cancer which is progressing while a decrease or equivalent level of LSG measured m the patient versus the control can be associated with a cancer which is regressing or m remission.
  • Another object of the present invention is to provide a method of monitoring lung cancer in a patient for the onset of metastasis.
  • the method comprises identifying a patient having lung cancer that is not known to have metastasized, periodically measuring levels of LSG m a sample of cells, tissues, or bodily fluid obtained from the patient, and comparing the measured LSG levels with levels of LSG in preferably the same cells, tissue, or bodily fluid type of a control, wherein an increase m measured LSG levels versus control LSG levels is associated with a cancer which has metastasized.
  • Yet another object of the present invention is to provide a method of monitoring the change in stage of lung cancer m a patient which comprises identifying a patient having lung cancer, periodically measuring levels of LSG in a sample of cells, tissue, or bodily fluid obtained from the patient, and comparing the measured LSG levels with levels of LSG in preferably the same cells, tissues, or bodily fluid type of a control wherein an increase in measured LSG levels versus the control LSG levels is associated with a cancer which is progressing and a decrease in the measured LSG levels versus the control LSG levels is associated with a cancer which is regressing or m remission.
  • the present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging, and prognosticating cancers by comparing levels of LSG with those of LSG in a normal human control.
  • levels of LSG as used herein, means levels of the native protein expressed by the gene comprising the polynucleotide sequence of any of SEQ ID NO: 1, 2, 3, 4, 5, or 6.
  • level of LSG means levels of the native mRNA encoded by the gene comprising any of the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6 or levels of the gene comprising any of the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.
  • levels are preferably measured in at least one of, cells, tissues and/or bodily fluids, including determination of normal and abnormal levels.
  • a diagnostic assay in accordance with the invention for diagnosing over-expression of LSG protein compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of cancers, including lung cancer. Any of the six LSGs may be measured alone in the methods of the invention, or all together or any combination of the six.
  • control it is meant a human patient without cancer and/or non cancerous samples from the patient, also referred to herein as a normal human control; in the methods for diagnosing or monitoring for metastasis, control may also include samples from a human patient that is determined by reliable methods to have lung cancer which has not metastasized.
  • All the methods of the present invention may optionally include measuring the levels of other cancer markers as well as LSG.
  • Other cancer markers, in addition to LSG, useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. Diagnostic Assays
  • the present invention provides methods for diagnosing the presence of lung cancer by analyzing for changes in levels of LSG in cells, tissues or bodily fluids compared with levels of LSG in cells, tissues or bodily fluids of preferably the same type from a normal human control, wherein an increase in levels of LSG in the patient versus the normal human control is associated with the presence of lung cancer.
  • a positive result indicating the patient being tested has cancer is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as LSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal human control.
  • the cancer marker such as LSG
  • the present invention also provides a method of diagnosing metastatic lung cancer in a patient having lung cancer which has not yet metastasized for the onset of metastasis.
  • a human cancer patient suspected of having lung cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art.
  • patients are typically diagnosed with lung cancer following traditional detection methods .
  • determining the presence of LSG level in cells, tissues, or bodily fluid is particularly useful for discriminating between lung cancer which has not metastasized and lung cancer which has metastasized.
  • Existing techniques have difficulty discriminating between lung cancer which has metastasized and lung cancer which has not metastasized and proper treatment selection is often dependent upon such knowledge.
  • the cancer marker levels measured in such cells, tissues, or bodily fluid is LSG, and are compared with levels of LSG in preferably the same cells, tissue, or bodily fluid type of a normal human control. That is, if the cancer marker being observed is just LSG in serum, this level is preferably compared with the level of LSG in serum of a normal human patient. An increase in the LSG in the patient versus the normal human control is associated with lung cancer which has metastasized.
  • a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as LSG, are at least two times higher, and most preferable are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal patient.
  • the invention also provides a method of staging lung cancer in a human patient.
  • the method comprises identifying a human patient having such cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for LSG. Then, the method compares LSG levels in such cells, tissues, or bodily fluid with levels of LSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in LSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of LSG is associated with a cancer which is regressing or in remission.
  • Moni toring Moni toring
  • the method comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for LSG; comparing the LSG levels in such cells, tissue, or bodily fluid with levels of LSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in LSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
  • the method comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for LSG; comparing the LSG levels in such cells, tissue, or bodily fluid with levels of LSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in LSG levels in the patient versus the normal human control is associated with a cancer which is progressing in stage and a decrease in the levels of LSG is associated with a cancer which is regressing in stage or in remission.
  • Assay techniques that can be used to determine levels of gene expression, such as LSG of the present invention, in a sample derived from a host are well-known to those of skill m the art.
  • Such assay methods include radioimmunoassays, reverse transcriptase PCR (RT-PCR) assays, immunohistochemistry assays, in si tu hybridization assays, competitive-binding assays, Western Blot analyses and ELISA assays.
  • RT-PCR reverse transcriptase PCR
  • immunohistochemistry assays in si tu hybridization assays
  • competitive-binding assays in si tu hybridization assays
  • Western Blot analyses Western Blot analyses
  • ELISAs are frequently preferred to diagnose a gene's expressed protein m biological fluids.
  • An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to LSG, preferably a monoclonal antibody.
  • a reporter antibody generally is prepared which binds specifically to LSG.
  • the reporter antibody is attached to a detectable reagent such as radioactive, fluorescent or enzymatic reagent, for example horseradish peroxidase enzyme or alkaline phosphatase.
  • a solid support e.g., a polystyrene dish
  • Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin.
  • the sample to be analyzed is incubated in the dish, during which time LSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer.
  • a reporter antibody specifically directed to LSG and linked to horseradish peroxidase is placed in the dish resulting m binding of the reporter antibody to any monoclonal antibody bound to LSG. Unattached reporter antibody is then washed out.
  • Reagents for peroxidase activity including a colorimetric substrate are then added to the dish.
  • the amount of color developed in a given time period is proportional to the amount of LSG protein present in the sample.
  • Quantitative results typically are obtained by reference to a standard curve .
  • a competition assay may be employed wherein antibodies specific to LSG attached to a solid support and labeled LSG and a sample derived from the host are passed over the solid support and the amount of label detected attached to the solid support can be correlated to a quantity of LSG in the sample.
  • Nucleic acid methods may be used to detect LSG mRNA as a marker for lung cancer.
  • Polymerase chain reaction (PCR) and other nucleic acid methods such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASABA)
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • NASABA nucleic acid sequence based amplification
  • RT-PCR reverse- transcriptase PCR
  • cDNA complementary DNA
  • RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the mRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence of a specific type of cell.
  • Hybridization to clones or oligonucleotides arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of that gene.
  • a cDNA encoding the LSG gene is fixed to a substrate.
  • the substrate may be of any suitable type including but not limited to glass, nitrocellulose, nylon or plastic.
  • At least a portion of the DNA encoding the LSG gene is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA, isolated from the tissue of interest.
  • Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including but not limited to radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed to detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards. The standards can be obtained by in vitro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
  • Bodily fluids useful in the present invention include blood, urine, saliva, or any other bodily secretion or derivative thereof.
  • Blood can include whole blood, plasma, serum, or any derivative of blood.
  • Library Comparison (compares one library to one other library) allows the identification of clones expressed in tumor and absent or expressed at a lower level in normal tissue .
  • Subsetting is similar to library comparison but allows the identification of clones expressed in a pool of libraries and absent or expressed at a lower level in a second pool of libraries.
  • Transcript Imaging lists all of the clones in a single library or a pool of libraries based on abundance. Individual clones can then be examined using Electronic Northerns to determine the tissue sources of their component ESTs.
  • Incyte has identified subsets of ESTs with a potential protein function based on homologies to known proteins. Some examples in this database include Transcription Factors and Proteases. Some lead were identified by searching in this database for clones whose component EST's showed disease specificity.
  • Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase.
  • the method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5' reporter dye and a downstream, 3' quencher dye.
  • Taqman internal fluorescent oligonucleotide probe
  • the 5' -3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, CA, USA) .
  • Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency.
  • Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or 18S ribosomal RNA (rRNA) is used as this endogenous control.
  • GPDH glyceraldehyde-3-phosphate dehydrogenase
  • rRNA 18S ribosomal RNA
  • RNA was extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues.
  • first strand cDNA was prepared with reverse transcriptase and the polymerase chain reaction was done using primers and Taqman probe specific to each target gene.
  • the results are analyzed using the ABI PRISM 7700 Sequence Detector.
  • the absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue. Comparative Examples
  • PSA Prostate Specific Antigen
  • PLA2 Phospholipase A2
  • the relative levels of expression in Table 2 show that mRNA expression of the LSG LnglOl (SEQ ID NO:l) is very high (72716) in lung compared with all the other normal tissues analyzed.
  • Testis, the calibrator, with a relative expression level of 1, heart (1.55), and mammary gland (2) are the only tissues expressing the mRNA for LnglOl.
  • the absolute numbers in Table 2 were obtained analyzing pools of samples of a particular tissue from different individuals. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 3.
  • Table 3 The absolute numbers depicted in Table 3 are relative levels of expression of LnglOl in 44 pairs of matching samples. All the values are compared to normal testis (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. Table 3 : Relative Levels of LnglOl Expression in Individual Samples
  • the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent).
  • Table 3 shows overexpression of LSG LnglOl in 6 lung cancer tissues compared with their respective normal adjacent (lung samples #4, 8, 10, 14, 16, and 18) . There was overexpression in the cancer tissue for 30% of the lung matching samples tested (total of 20 lung matching samples) .
  • LSG LnglOl SEQ ID NO:l
  • SEQ ID NO: 7 The amino acid sequence encoded by LnglOl (SEQ ID NO:l) is depicted in SEQ ID NO: 7.
  • Table 4 The absolute numbers depicted in Table 4 are relative levels of expression of LSG Lngl05 (SEQ ID NO: 3) in 12 normal different tissues. All the values are compared to normal kidney (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals. Table 4 : Relative levels of Lngl05 Expression in Pooled Samples
  • the absolute numbers in Table 4 were obtained analyzing pools of samples of a particular tissue from different individuals. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 5.
  • the absolute numbers depicted in Table 5 are relative levels of expression of Lngl05 (SEQ ID NO: 3) in 61 pairs of matching samples. All the values are compared to normal small intestine (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. Table 5 : Relative Levels of Lngl05 Expression in Individual Samples
  • the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 5 shows overexpression of LSG Lngl05 (SEQ ID NO: 3) in 13 lung cancer tissues compared with their respective normal adjacent (lung samples #1, 3, 5, 8, 9, 10, 11, 12, 20, 21, 22, 24, and 25). There is overexpression in the cancer tissue for 46% of the colon matching samples tested (total of 28 lung matching samples) .
  • Lngl05 SEQ ID NO: 3
  • SEQ ID NO: 8 The amino acid sequence encoded by Lngl05 (SEQ ID NO: 3) is depicted as SEQ ID NO: 8.
  • RNA samples depicted in Table 6 are relative levels of expression of LSG Lngl07 (SEQ ID NO: 6) in 12 normal different tissues. All the values are compared to normal mammary gland (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the absolute numbers in Table 6 were obtained analyzing pools of samples of a particular tissue from different individuals. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 7.
  • the absolute numbers depicted in Table 7 are relative levels of expression of LSG Lngl07 (SEQ ID NO: 6) in 57 pairs of matching samples. All the values are compared to normal prostate (calibrator) .
  • a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual.
  • the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 7 shows overexpression of LSG Lngl07 (SEQ ID NO: 6) in 15 lung cancer tissues compared with their respective normal adjacent (lung samples #1, 3, 4, 5, 7, 8, 9, 10, 11, 14, 15, 18, 19, 20, and 22) . There is overexpression in the cancer tissue for 57% of the lung matching samples tested (total of 26 lung matching samples) .
  • Lngl07 being a diagnostic marker for lung cancer.
  • the amino acid sequence encoded by Lngl07 is depicted in SEQ ID NO: 9.

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Abstract

La présente invention concerne une technique permettant de faire la détection, le diagnostic, le suivi, la stadification et le progonostic du cancer du poumon.
PCT/US1999/010344 1998-05-21 1999-05-12 Technique de diagnostic, de suivi et de stadification du cancer du poumon WO1999060160A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US09/700,770 US7160679B1 (en) 1998-05-21 1999-05-12 Method of diagnosing, monitoring, and staging lung cancer
CA002328138A CA2328138A1 (fr) 1998-05-21 1999-05-12 Technique de diagnostic, de suivi et de stadification du cancer du poumon
JP2000549766A JP3688585B2 (ja) 1998-05-21 1999-05-12 肺癌を診断し、モニターし、そして病期決定する新規方法
EP99921894A EP1082459A4 (fr) 1998-05-21 1999-05-12 Technique de diagnostic, de suivi et de stadification du cancer du poumon

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US8621298P 1998-05-21 1998-05-21
US60/086,212 1998-05-21

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WO1999060160A1 true WO1999060160A1 (fr) 1999-11-25

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001053349A3 (fr) * 2000-01-21 2002-01-10 Ludwig Inst Cancer Res Antigenes associes au cancer du poumon a petites cellules et utilisations de ces antigenes
EP1104486A4 (fr) * 1998-08-04 2002-07-17 Diadexus Llc Nouveau procede de diagnostic, de surveillance, de classification par stades, d'imagerie et de traitement du cancer des poumons
WO2001072775A3 (fr) * 2000-03-29 2002-08-22 Diadexus Inc Compositions et methodes de diagnostic, de surveillance, de stadification, d'imagerie, et de traitement du cancer du poumon
WO2001061055A3 (fr) * 2000-02-17 2002-08-29 Diadexus Inc Procedes de diagnostic, de monitorage, de stadage, d'imagerie et de traitement du cancer du poumon par le biais de genes specifiques du cancer du poumon
EP1109937A4 (fr) * 1998-09-02 2002-09-25 Diadexus Inc Nouveau procede de diagnostic, de surveillance, de classification par stades, d'imagerie et de traitement de divers cancers
WO2002008278A3 (fr) * 2000-07-21 2003-03-13 Diadexus Inc Compositions et procedes relatifs aux genes specifiques aux poumons
WO2002068633A3 (fr) * 2000-11-22 2003-03-27 Diadexus Inc Compositions et procedes concernant des genes et proteines specifiques aux poumons
WO2002018576A3 (fr) * 2000-08-28 2003-04-17 Diadexus Inc Compositions et methodes associees aux genes specifiques du poumon
WO2002077236A3 (fr) * 2000-10-26 2003-08-21 Diadexus Inc Compositions et procedes associes aux genes et aux proteines specifiques du poumon
WO2002092858A3 (fr) * 2001-05-17 2003-10-30 Exact Sciences Corp Technique de recherche de maladie
EP1453977A4 (fr) * 2001-08-16 2005-04-20 Us Health Caracteristiques moleculaires du cancer du poumon non a petites cellules
US6964846B1 (en) 1999-04-09 2005-11-15 Exact Sciences Corporation Methods for detecting nucleic acids indicative of cancer
WO2006013012A3 (fr) * 2004-08-04 2006-04-06 Bayer Healthcare Ag Diagnostics et therapeutique pour maladies liees a la napsine 1 (nap1)
US7160679B1 (en) 1998-05-21 2007-01-09 Diadexus, Inc. Method of diagnosing, monitoring, and staging lung cancer
AU2002236618B2 (en) * 2001-02-28 2007-08-09 Genentech, Inc. Interleukin-8 homologous polypeptides and therapeutic uses thereof
US7291712B2 (en) 1998-06-25 2007-11-06 Genentech, Inc. Interleukin-8 homologous polypeptides and therapeutic uses thereof
EP1873245A1 (fr) * 2001-02-28 2008-01-02 Genentech, Inc. Polypeptides homologue à l'interleukine-8 et utilisations thérapeutiques correspondantes
US7425607B2 (en) 1999-06-30 2008-09-16 Corixa Corporation Compositions comprising a lung tumor antigen
EP2399995A3 (fr) * 2002-11-22 2012-08-08 Ganymed Pharmaceuticals AG Produits géniques d'expression différentielle dans les tumeurs et leur utilisation
US9109256B2 (en) 2004-10-27 2015-08-18 Esoterix Genetic Laboratories, Llc Method for monitoring disease progression or recurrence
US9777314B2 (en) 2005-04-21 2017-10-03 Esoterix Genetic Laboratories, Llc Analysis of heterogeneous nucleic acid samples
US9920374B2 (en) 2005-04-14 2018-03-20 Trustees Of Boston University Diagnostic for lung disorders using class prediction
US10526655B2 (en) 2013-03-14 2020-01-07 Veracyte, Inc. Methods for evaluating COPD status
US10570454B2 (en) 2007-09-19 2020-02-25 Trustees Of Boston University Methods of identifying individuals at increased risk of lung cancer
US10731223B2 (en) 2009-12-09 2020-08-04 Veracyte, Inc. Algorithms for disease diagnostics
US10927417B2 (en) 2016-07-08 2021-02-23 Trustees Of Boston University Gene expression-based biomarker for the detection and monitoring of bronchial premalignant lesions
US11639527B2 (en) 2014-11-05 2023-05-02 Veracyte, Inc. Methods for nucleic acid sequencing
US11977076B2 (en) 2006-03-09 2024-05-07 Trustees Of Boston University Diagnostic and prognostic methods for lung disorders using gene expression profiles from nose epithelial cells
US11976329B2 (en) 2013-03-15 2024-05-07 Veracyte, Inc. Methods and systems for detecting usual interstitial pneumonia
US12110554B2 (en) 2009-05-07 2024-10-08 Veracyte, Inc. Methods for classification of tissue samples as positive or negative for cancer
US12297505B2 (en) 2014-07-14 2025-05-13 Veracyte, Inc. Algorithms for disease diagnostics
US12305238B2 (en) 2008-11-17 2025-05-20 Veracyte, Inc. Methods for treatment of thyroid cancer

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Cited By (40)

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US7160679B1 (en) 1998-05-21 2007-01-09 Diadexus, Inc. Method of diagnosing, monitoring, and staging lung cancer
US7291712B2 (en) 1998-06-25 2007-11-06 Genentech, Inc. Interleukin-8 homologous polypeptides and therapeutic uses thereof
EP1104486A4 (fr) * 1998-08-04 2002-07-17 Diadexus Llc Nouveau procede de diagnostic, de surveillance, de classification par stades, d'imagerie et de traitement du cancer des poumons
JP3524061B2 (ja) 1998-08-04 2004-04-26 ダイアデクスアス・インコーポレーテッド 肺がんを診断し、モニターし、病期決定し、画像化し、そして処置する新規な方法
EP1109937A4 (fr) * 1998-09-02 2002-09-25 Diadexus Inc Nouveau procede de diagnostic, de surveillance, de classification par stades, d'imagerie et de traitement de divers cancers
EP2053129A3 (fr) * 1998-09-02 2009-08-19 Diadexus, Inc. Procédé de diagnostic, surveillance, stratification, imagerie et traitement de divers cancers
US6964846B1 (en) 1999-04-09 2005-11-15 Exact Sciences Corporation Methods for detecting nucleic acids indicative of cancer
US7425607B2 (en) 1999-06-30 2008-09-16 Corixa Corporation Compositions comprising a lung tumor antigen
WO2001053349A3 (fr) * 2000-01-21 2002-01-10 Ludwig Inst Cancer Res Antigenes associes au cancer du poumon a petites cellules et utilisations de ces antigenes
US7314721B2 (en) 2000-01-21 2008-01-01 Ludwig Institute For Cancer Research Small cell lung cancer associated antigens and uses therefor
WO2001061055A3 (fr) * 2000-02-17 2002-08-29 Diadexus Inc Procedes de diagnostic, de monitorage, de stadage, d'imagerie et de traitement du cancer du poumon par le biais de genes specifiques du cancer du poumon
WO2001072775A3 (fr) * 2000-03-29 2002-08-22 Diadexus Inc Compositions et methodes de diagnostic, de surveillance, de stadification, d'imagerie, et de traitement du cancer du poumon
WO2002008278A3 (fr) * 2000-07-21 2003-03-13 Diadexus Inc Compositions et procedes relatifs aux genes specifiques aux poumons
WO2002018576A3 (fr) * 2000-08-28 2003-04-17 Diadexus Inc Compositions et methodes associees aux genes specifiques du poumon
WO2002077236A3 (fr) * 2000-10-26 2003-08-21 Diadexus Inc Compositions et procedes associes aux genes et aux proteines specifiques du poumon
WO2002068633A3 (fr) * 2000-11-22 2003-03-27 Diadexus Inc Compositions et procedes concernant des genes et proteines specifiques aux poumons
AU2002236618B2 (en) * 2001-02-28 2007-08-09 Genentech, Inc. Interleukin-8 homologous polypeptides and therapeutic uses thereof
EP1366161B1 (fr) * 2001-02-28 2007-10-03 Genentech, Inc. Anticorps antagoniste contre le pro842
EP1873245A1 (fr) * 2001-02-28 2008-01-02 Genentech, Inc. Polypeptides homologue à l'interleukine-8 et utilisations thérapeutiques correspondantes
WO2002092858A3 (fr) * 2001-05-17 2003-10-30 Exact Sciences Corp Technique de recherche de maladie
US7332590B2 (en) 2001-08-16 2008-02-19 The United States Of America As Represented By The Department Of Health And Human Services Molecular characteristics of non-small cell lung cancer
EP1453977A4 (fr) * 2001-08-16 2005-04-20 Us Health Caracteristiques moleculaires du cancer du poumon non a petites cellules
US7709202B2 (en) 2001-08-16 2010-05-04 The Johns Hopkins University Molecular characteristics of non-small cell lung cancer
EP2399995A3 (fr) * 2002-11-22 2012-08-08 Ganymed Pharmaceuticals AG Produits géniques d'expression différentielle dans les tumeurs et leur utilisation
WO2006013012A3 (fr) * 2004-08-04 2006-04-06 Bayer Healthcare Ag Diagnostics et therapeutique pour maladies liees a la napsine 1 (nap1)
US9109256B2 (en) 2004-10-27 2015-08-18 Esoterix Genetic Laboratories, Llc Method for monitoring disease progression or recurrence
US10808285B2 (en) 2005-04-14 2020-10-20 Trustees Of Boston University Diagnostic for lung disorders using class prediction
US9920374B2 (en) 2005-04-14 2018-03-20 Trustees Of Boston University Diagnostic for lung disorders using class prediction
US9777314B2 (en) 2005-04-21 2017-10-03 Esoterix Genetic Laboratories, Llc Analysis of heterogeneous nucleic acid samples
US11977076B2 (en) 2006-03-09 2024-05-07 Trustees Of Boston University Diagnostic and prognostic methods for lung disorders using gene expression profiles from nose epithelial cells
US10570454B2 (en) 2007-09-19 2020-02-25 Trustees Of Boston University Methods of identifying individuals at increased risk of lung cancer
US12305238B2 (en) 2008-11-17 2025-05-20 Veracyte, Inc. Methods for treatment of thyroid cancer
US12110554B2 (en) 2009-05-07 2024-10-08 Veracyte, Inc. Methods for classification of tissue samples as positive or negative for cancer
US12297503B2 (en) 2009-05-07 2025-05-13 Veracyte, Inc. Methods for classification of tissue samples as positive or negative for cancer
US10731223B2 (en) 2009-12-09 2020-08-04 Veracyte, Inc. Algorithms for disease diagnostics
US10526655B2 (en) 2013-03-14 2020-01-07 Veracyte, Inc. Methods for evaluating COPD status
US11976329B2 (en) 2013-03-15 2024-05-07 Veracyte, Inc. Methods and systems for detecting usual interstitial pneumonia
US12297505B2 (en) 2014-07-14 2025-05-13 Veracyte, Inc. Algorithms for disease diagnostics
US11639527B2 (en) 2014-11-05 2023-05-02 Veracyte, Inc. Methods for nucleic acid sequencing
US10927417B2 (en) 2016-07-08 2021-02-23 Trustees Of Boston University Gene expression-based biomarker for the detection and monitoring of bronchial premalignant lesions

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EP1082459A4 (fr) 2002-09-25
CA2328138A1 (fr) 1999-11-25
EP1082459A1 (fr) 2001-03-14
JP2002515262A (ja) 2002-05-28
JP3688585B2 (ja) 2005-08-31

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