WO1999001581A1 - Expression genetique influencee par p53 - Google Patents

Expression genetique influencee par p53 Download PDF

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WO1999001581A1
WO1999001581A1 PCT/US1998/013903 US9813903W WO9901581A1 WO 1999001581 A1 WO1999001581 A1 WO 1999001581A1 US 9813903 W US9813903 W US 9813903W WO 9901581 A1 WO9901581 A1 WO 9901581A1
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tissue
sample
transcript
genes
transcription
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PCT/US1998/013903
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Stephen L. Madden
Elizabeth A. Galella
Arthur H. Bertelsen
Gary A. Beaudry
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Genzyme Corporation
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Priority to AU83829/98A priority Critical patent/AU8382998A/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/142—Toxicological screening, e.g. expression profiles which identify toxicity

Definitions

  • This invention is related to genes and proteins involved in cell cycle control and tumorigenesis. KAr ⁇ ;ttn ⁇ Nn o ⁇ TTTK TNV TTQN
  • Transcriptional regulation mediated by the p53 tumor suppressor gene product is implicated in numerous cell regulatory cascades, most prominently cell growth regulation (White, 1996; Ko & Prives, 1996). While many genes have been shown to be transcriptionally regulated by p53 either directly (MDM2, p21 AF1/CIP1 , cyclin G, GADD45, IGFBP3, BAX, IGF-IR) or indirectly (Thrombospondin-1, TGF-c , PCNA, c-fos, c-jun, HSP70) (see Ko & Prives, 1996 for review), the cellular context required for specific p53-mediated transcriptional regulation remains ill-defined.
  • Rat embryo fibroblast (REF) cells transformed with activated RAS and a mouse temperature-sensitive p53 (Vall35) gene constitute a tightly regulated, well defined system to study mechanisms involved in p53-mediated cell growth regulation (Michalovitz et al., 1990; Pietenpol et al., 1996; Martinez et al., 1991).
  • Transformed REF cells grown at the non-permissive temperature (38°C) maintain the p53 protein in a non-functional conformation confined to the cytoplasm of the cell.
  • Another object of the invention is to provide a method for evaluating cytotoxicity or carcinogenicity of an agent.
  • a method for diagnosing cancer in a sample suspected of being neoplastic comprises the steps of: comparing the level of transcription of an RNA transcript in a first sample of a first tissue to the level of transcription of the transcript in a second sample of a second tissue, wherein the first tissue is suspected of being neoplastic and the second tissue is a normal human tissue, wherein the first and second tissue are of the same tissue type, and wherein the transcript is selected from the group consisting of Alu, RAS, U6 snRNA, 16S RNA, EGR-1, ribosomal protein S27, ETS-1, 28S RNA, CGR11, and LIMK-2; categorizing the first sample as neoplastic when transcription is found to be lower in the first sample than in the second sample.
  • a method for diagnosing cancer in a sample suspected of being neoplastic comprises the steps of: comparing the level of transcription of an RNA transcript in a first sample of a first tissue to the level of transcription of the transcript in a second sample of a second tissue, wherein the first tissue is suspected of being neoplastic and the second tissue is ⁇ t normal human tissue, wherein the first and second tissue are of the same tissue type, and wherein the transcript is identified by a tag selected from the group consisting of ribosomal protein L13a, -tubulin (1), ⁇ -tubulin (2), thymosin ⁇ -4, and ⁇ -actin; categorizing the first sample as neoplastic when transcription is found to be higher in the first sample than in the second sample.
  • nucleic acid molecule comprises a SAGE tag selected from the group consisting of SEQ ID NOS: 11-16, 21-23, 25-28, 35-37, and 39-40.
  • an isolated nucleotide probe comprises at least 12 nucleotides of a rat nucleic acid molecule, wherein the rat nucleic acid molecule comprises a SAGE tag selected from the group consisting of SEQ ID NOS: 11-16, 21-23, 25-28, 35-37, and 39-40.
  • a method is provided for evaluating cytotoxicity or carcinogenicity of an agent.
  • the method comprises the steps of: contacting a test agent with a rat cell; determining the level of transcription of a transcript in the rat cell after contacting with the agent; wherein an agent which decreases the level of a transcript identified by a SAGE tag as shown in SEQ ID NOS: 1-28, or an agent which increases the level of a transcript identified by a SAGE tag as shown in SEQ ID NOS:29-40 is a potential cytotoxin or carcinogen.
  • Figure 1 Cumulative total gene representation within the REF SAGE analysis. Sequenced SAGE tag (transcripts) accumulation was monitored for unique tags (genes) sporadically throughout the analysis using the SAGE software package.
  • the genes which are identified as being upregulated or downregulated by p53 can be used to diagnose cancer in a sample.
  • the sample can be a tissue sample isolated from a human which is suspected of being neoplastic.
  • the level of transcription of an RNA can be determined and compared to the level in a normal tissue, preferably of the same tissue source.
  • Techniques for determining levels of transcription of an RNA are well known in the art, and include, without limitation, Northern blots, nuclear run-on assays, in vitro transcription assays, primer extension assays, quantitative reverse transcriptase-polymerase chain reactions (RT-PCR), and hybrid filter binding assays. These techniques are well known in the art. See J.C. Alwine, D.J. Kemp, G.R.
  • transcripts identified herein as being up- or down-regulated by p53 When a transcript identified herein as being up- or down-regulated by p53 is found to be either up- or down-regulated in the test sample, then the sample can be categorized as neoplastic.
  • Transcripts which are identified herein as being down- regulated in the absence of p53 are Alu, RAS, U6 snRNA, 16S RNA, EGR-1, ribosomal protein S27, ETS-1, 28S RNA, CGR11, and LIMK-2.
  • Transcripts which are identified as being in the absence of p53 are ribosomal protein L13a, ⁇ -tubulin (1), ⁇ -tubulin (2), thymosin ⁇ -4, and ⁇ -actin.
  • transcipts can be assayed.
  • level of at least two, five, six, or ten of the transcripts can be determined.
  • Assays involving both up-regulated and down- regulated transcripts can be combined.
  • transcripts which have been identified herein on the basis of their up-or down-regulation in the absence of p53. These transcripts are identified by the SAGE tags shown in SEQ ID NOS: 11-16, 21-23, 25-28, 35-37, and 39-40. Given the SAGE tags is well within the skill of the art to isolate the RNA or cDNA which contains the SAGE tag. Due to the method of isolation of SAGE tags, they occur only in the 3' end of transcripts, immediately adjacent to the restriction enzyme site of the enzyme which was used to generate the SAGE tags. Thus hybridization under stringent conditions to cDNA libraries can be used to select larger cDNAs which contain the SAGE tag.
  • SAGE tags isolated herein are derived from rat cells, similar sequences from other mammals, including humans, can be obtained using hybridization with the SAGE tags themselves, or using other portions of the rat genes identified by the SAGE tags.
  • Probes comprising at least 10, 12, 14, 16, 18, 20, 25, or 30 contiguous nucleotides of the cDNA identified by the SAGE tags can be used as probes.
  • the probe may or may not contain the sequence of the SAGE tag.
  • the probes can be labeled, as is known in the art, using for example, radiolabels, fluorescent labels, or enzymatic labels. These probes can be used to identify and isolate the homologues from related mammalian species.
  • the probes can also be used to directly assay in humans or other mammals for up-or down-regulation in a sample of the corresponding transcript. Such regulation can be used as an indicator of neoplasia, as discussed above.
  • Combinations of probes can be provided in single or multiple vials as reagents for evaluating toxicity or carcinogencity of test compounds.
  • the reagents can be provided in a kit, which optionally contains instructions for performing the assays, buffers, growth media, cells, detection reagents.
  • the level of transcription of a transcript in a rat cell is determined after the rat cell has been contacted with the test compound.
  • the effect of the test compound on transcription of the transcript identified by the probe is determined.
  • Test compounds which cause changes in the transcript levels which mimic the changes caused by loss of p53 are identified as potential cototoxins or carcinogens.
  • this transcript represents an alternative form of cyclin G RNA that gives rise to the apparently "internal" SAGE tag.
  • the combined abundance of the cyclin G transcripts is " 0-.34% of the total cDNA. While the significance of the two highly expressed tags and function of cyclin G remain undefined, such high levels of expression suggests cyclin G plays a major role in regulating cell growth of wild-type p53-containing REF cells. Finally, the presence of rRNA sequence tags results from the likely incomplete separation of mRNA from the rRNA population during library generation. Subsequent oligo(dT)-priming of dA-rich regions within specific rRNA's would result in rRNA-specific tags within the SAGE library.
  • TJ6 snRNA The differential expression observed for TJ6 snRNA raises some interesting questions. Theoretically, the detection of this small RNA molecule should not be possible with oligo(dT)-dependent priming. While 3' modifications have been shown to occur to the U6 snRNA molecule, these modifications do not include base additions that facilitate oligo-dT priming (Lund & Dahlberg, 1992).
  • One possible explanation for the observed differential detection of TJ6 snRNA is that upon apoptotic nuclear breakdown the U6 snRNA is liberated from the nucleus and fortuitously polyadenylated. No other snRNA species were detected in the SAGE analysis.
  • the EGR-1 transcription factor accounts for 0.1 % of REF mRNA at 32°C.
  • This well characterized transcriptional activator and repressor has been shown to be regulated in response to a wide array of growth regulatory stimuli, initially being described as an early growth response gene activated by serum (Sukhatme et al. , 1988; Cao et al., 1990).
  • Initial studies on EGR-1 appeared to correlate expression with enhanced cellular proliferation, however, more recently a role of EGR1 in cellular differentiation has been proposed (Bains, 1996), similar to the role proposed for p21 WAF1/CIP1 in myogenic differentiation (Liu et al., 1996).
  • EGR-1 induction observed in wild-type p53 REF cells stems from the triggering of molecular mechanisms similar to differentiation. Further, as some of the wild-type p53-containing REF cells are undergoing apoptosis, the identification of elevated levels of EGR-1 in these cells may indicate a more prominent role for EGR-1 in programmed cell death than previously appreciated.
  • REF-Phel32 control cells identified a small number of genes whose expression was apparently elevated in the REF-Phel32 mRNA population with respect to both 32°C and 38 C-maintained REF-Vall35 cells (galectin-1 [Perillo et al., 1995], MTS1 [Ambartsumian et al., 1995], TRPM-2 [apolipoprotein J/clusterin] (Wright et al., 1996), osteopontin [Oates et al., 1996]).
  • REF-Phel32-specific regulated genes could potentially represent unique transcriptional regulation dependent on specific p53 mutant proteins. Experiments by other investigators (Chen et al.
  • Control REF cells transformed with Ha-RAS and non-temperature-sensitive mutant p53 REF cells do not exhibit growth arrest or apoptosis at the permissive temperature (32°C) (Ginsberg et al., 1991; Michalovitz et al., 1990).
  • permissive temperature 32°C
  • Rat embryo fibroblast cells REF-Vall35 (temperature-sensitive) and REF-Phel32 (provided by B. Vogelstein and M. Oren, see Ginsberg et al., 1991; Michalovitz et al., 1990) were maintained in DMEM containing 10% fetal bovine serum in 5% CO 2 at either 32°C or 38°C. Cells were trypsinized and replated at least 48 hours prior to any temperature shift. Temperature shifts were made by transfer of subconfluent flasks to pre-equilibrated incubators without media changes. RNA was harvested 8 hours after shift to 32°C.
  • SAGE libraries were generated using 2.5 ug polyA + RNA and the restriction enzyme NlalU as described (Velculescu et al. , 1995) except that the concatamers were cloned into Sphl-digested pZErO-1 (InVitrogen).
  • cDNA libraries were constructed using a ⁇ ZapExpress system (Stratagene) according to the manufacturer's instructions.
  • Hybridizations to ⁇ clones were performed using either a 14 base or 15 base oligonucleotide end-labeled with 32 P (Velculescu et al., 1995). Some clones were obtained using the GeneTrapper kit (Gibco/BRL) and 15 base pair oligomers derived from the SAGE tag. Plasmids. Rat clones for p21 WAF1/CIP and MDM2 (provided by B. Vogelstein) were sequenced to determine respective SAGE tags. The 3 '-most NlalU sites are CATG/TATTTTGGTC and CATG/ATTTAGCAGT for p 21 WAF1 CIP1 and MDM2, respectively.
  • the rat p21 WAF1/CIP sequence which juxtaposes the NlaUJ and BsmFI sites is 5'-CATGTATTTTGGTCCC-3'.
  • Adaptor ligation to Nlal ⁇ -digested rat p21 WAF1 CIP1 generates a second BsmFI site 5' to the endogenous BsmFI site ultimately resulting in a reduction of the p21 WAF1 CIP tags observed in the SAGE library.
  • REF-Vall35 REF cells transformed with RAS phis temperature sensitive p53.
  • REF-Phel32 REF cells transformed with RAS phis Phel32-p53. f Cumulative numbers are presented for a combined analysis of sequences from the two (32°C + 38°C) Vall35 libraries.
  • Sequences from each of the Vall35 cDNA libraries represented more than 9,000 different genes, with about 3,000 being represented more than once in either library.
  • Combined analysis of transcripts from both 32°C and 38'C REF-Vall35 cDNA identified more than 15,000 different genes with more than 5,000 genes represented more than one time.
  • Figure 1 details the increase in gene representation as the number of SAGE transcripts sequenced increases, demonstrating that many new transcripts are still being identified after 60,000 tags were sequenced.
  • the transcripts identified from control REF-Phel32 cDNA (> 10,000 SAGE tags) represent more than 5,000 genes with about 1,200 genes represented more than one time.
  • the three 38°C elevated tags represent ⁇ -actin (0.26%), ⁇ -tubulin (1 isoform, 0.25%), and HSP70 (0.21%) consistent with continuing growth of the 38°C-maintained cells.
  • the remaining 38°C-elevated tags include a second tubulin isoform, Thymosin ⁇ -4, ribosomal protein L13a, and several undefined genes.
  • CDK4 also showed a substantial differential induction in 38°C-induced cDNA (9 occurrences at 38°C and 1 occurrence at 32°C, p ⁇ 0.05).
  • the 14 genes expressed at elevated levels at 32°C include an alu repetitive tag (2.62%), RAS (0.95%), U6 snRNA (0.61 %), 2 cyclin G tags (0.18% and 0.16%), EGR-1 [Zif268/NGFI-A/Krox-24] (0.10%), external transcribed spacer-1 (ETS-1) (0.08%), a clone previously identified by subtractive hybridization (clone 13; B. Vogelstein and S. Zhou, personal communication) (0.07%), 28S rRNA (0.04%), CGR11 (0.04%), and 3 uncharacterized genes (clones 9, 12, 14; Table 2).
  • the genes corresponding to both cyclin G tags, U6 snRNA, and ETS-1 tags were cloned and verified to be expressed at the predicted SAGE abundance level (see below).
  • the p2l WAF1 CIP1 tag was present at 5 copies in the 32°C cDNA and 0 copies in the 38°C cDNA. This apparent low abundance of the p21 WAF1 CIP1 tag (0.04% vs. 0.20% expected) is apparently due to the presence of a site for the restriction endonuclease BsmFI within the p 2l AF1 CIP1 cDNA that overlaps the SAGE tag site.
  • genes showing elevated expression at 32°C include BAX1 (18:8), MDM2 (7:2), CGR19 (5:0), and another clone previously identified by subtractive hybridization (clone 50; B. Vogelstein and S. Zhou, personal communication) (5:0).
  • One measure of reproducibility of the transcript profiles involves comparison of transcript levels for genes encoding ribosomal proteins and known housekeeping genes. As shown in Table 2 for EF1 (327:396) and GAPDH (107:92), well-known housekeeping genes are expressed at comparable levels in both samples. Most ribosomal proteins were also present at similar levels in 32°C and 38°C cDNA (data not shown). As expected, exogenous p53 (mouse Vall35) also showed similar abundance in 32°C (46 tags) and 38°C (32 tags) cDNA populations (Table 2).
  • Partial cDNAs were obtained for three previously uncharacterized and relatively abundant rat tags at 32°C.
  • the clone 14 partial cDNA yielded an open reading frame (ORF) of 210 amino acids showing strong homology within a helix-loop-helix region to the HES transcription factor family (Sasai et al., 1992).
  • Clone 12 yielded an ORF of 149 amino acids likely to be the rat homologue of a previously identified human tissue specific protein (GenBank accession #X67698) of unknown function and clone 9 yielded an ORF of 164 amino acids with no homology to published proteins or protein motifs.
  • EXAMPLE 3 SAGE data for control, non-temperature-sensitive REF cells. SAGE analysis of the control REF-Phel32 cDNA generated from 32°C-maintained cells was performed to greater than 10,000 transcripts. With a few exceptions, the transcript profile from these cells resembled that generated from the REF-Vall35 38°C cDNA population (data not shown). One unknown gene was absent in the control REF-Phel32 cDNA but was expressed at about 0.10% in both the 32°C and 38°C REF-Vall35 cDNA populations.
  • RNA analyses were performed using either total or poly A + RNA and Ambion's NorthernMax kit. 32 P-labeled cDNA probes were generated by random-priming and hybridized and washed according to the manufacturer's protocol. Assurance of equivalent RNA loading was achieved either by UV shadowing (total RNA) or EFl probing (poly A + RNA).
  • Results show differential induction of all the unknown clones, U6 snRNA, cyclin G and ribosomal protein S27 in the 32°C mRNA population. As expected, the EFl probe revealed equal abundance in both populations. Thus, all SAGE transcript differentials also show similar differential expression by northern analysis, confirming representative sampling in the SAGE analysis.

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Abstract

L'analyse en série de l'expression génétique (SAGE) permet d'établir un profil quantitatif, représentatif et complet de l'expression génétique. La technologie SAGE a été utilisée pour distinguer le profil d'expression génétique différentiel de fibroblastes d'embryons de rat produisant la protéine thermosensible de suppression de tumeur p53, à des températures qui permettent cette production et à des températures qui ne la permettent pas. L'analyse d'~15000 gènes a révélé que l'expression de 14 gènes (p∫0,001, ≥0,03 % en nombre) dépend de la protéine p53 fonctionnelle, tandis que l'expression de 3 gènes est considérablement supérieure dans des cellules produisant la protéine p53 non fonctionnelle. Les gènes dont l'expression a été augmentée par p53 fonctionnelle comprennent RAS, petit ARN nucléaire U6, la cycline G, EGR-1, et plusieurs nouveaux gènes. L'expression d'actine, de tubuline, et de gènes HSP70 a été augmentée à une température ne permettant pas l'action de p53. De façon intéressante, l'expression de plusieurs gènes dépend d'une p53 mutante non thermosensible qui évoque des profils de transcription modifiés dépendant de protéines p53 mutantes spécifiques.
PCT/US1998/013903 1997-07-02 1998-07-02 Expression genetique influencee par p53 WO1999001581A1 (fr)

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Cited By (10)

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WO1999050456A1 (fr) * 1998-03-27 1999-10-07 Affymetrix, Inc. Genes a regulation p53
WO2001020998A1 (fr) * 1999-09-24 2001-03-29 Linden Technologies, Inc. Identification de medicaments au moyen d'un profilage de l'expression genique
WO2001051664A2 (fr) * 2000-01-12 2001-07-19 Dana-Farber Cancer Institute, Inc. Procede de detection et de caracterisation d'un neoplasme
WO2002010436A2 (fr) * 2000-07-28 2002-02-07 The Brigham And Women's Hospital, Inc. Classification de pronostics de cancer du sein
US6470277B1 (en) 1999-07-30 2002-10-22 Agy Therapeutics, Inc. Techniques for facilitating identification of candidate genes
WO2002099048A2 (fr) * 2001-06-05 2002-12-12 Exelixis, Inc. Genes limk en tant que modificateurs de la voie p53 et procedes d'utilisation associes
KR100375183B1 (ko) * 1999-09-21 2003-03-08 주식회사 삼양제넥스 사이클린 ｇ 또는 그것의 유전자를 이용한 자궁근종 진단방법 및 진단 키트
US6703204B1 (en) 2000-07-28 2004-03-09 The Brigham & Women's Hospital, Inc. Prognostic classification of breast cancer through determination of nucleic acid sequence expression
EP1534854A2 (fr) * 2002-03-28 2005-06-01 Medical college of Ohio Procede et compositions pour le diagnostic et le traitement du cancer bronchopulmonaire "non a petites cellules" au moyen de profiles d'expression genique
US8765368B2 (en) 2007-09-17 2014-07-01 The University Of Toledo Cancer risk biomarker

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020135A (en) * 1998-03-27 2000-02-01 Affymetrix, Inc. P53-regulated genes
US6171798B1 (en) 1998-03-27 2001-01-09 Affymetrix, Inc. P53-regulated genes
WO1999050456A1 (fr) * 1998-03-27 1999-10-07 Affymetrix, Inc. Genes a regulation p53
US6470277B1 (en) 1999-07-30 2002-10-22 Agy Therapeutics, Inc. Techniques for facilitating identification of candidate genes
KR100375183B1 (ko) * 1999-09-21 2003-03-08 주식회사 삼양제넥스 사이클린 ｇ 또는 그것의 유전자를 이용한 자궁근종 진단방법 및 진단 키트
WO2001020998A1 (fr) * 1999-09-24 2001-03-29 Linden Technologies, Inc. Identification de medicaments au moyen d'un profilage de l'expression genique
WO2001051664A2 (fr) * 2000-01-12 2001-07-19 Dana-Farber Cancer Institute, Inc. Procede de detection et de caracterisation d'un neoplasme
WO2001051664A3 (fr) * 2000-01-12 2002-09-06 Dana Farber Cancer Inst Inc Procede de detection et de caracterisation d'un neoplasme
US6703204B1 (en) 2000-07-28 2004-03-09 The Brigham & Women's Hospital, Inc. Prognostic classification of breast cancer through determination of nucleic acid sequence expression
WO2002010436A2 (fr) * 2000-07-28 2002-02-07 The Brigham And Women's Hospital, Inc. Classification de pronostics de cancer du sein
WO2002010436A3 (fr) * 2000-07-28 2003-07-03 Brigham & Womens Hospital Classification de pronostics de cancer du sein
WO2002099048A2 (fr) * 2001-06-05 2002-12-12 Exelixis, Inc. Genes limk en tant que modificateurs de la voie p53 et procedes d'utilisation associes
WO2002099048A3 (fr) * 2001-06-05 2004-07-22 Exelixis Inc Genes limk en tant que modificateurs de la voie p53 et procedes d'utilisation associes
EP1534854A2 (fr) * 2002-03-28 2005-06-01 Medical college of Ohio Procede et compositions pour le diagnostic et le traitement du cancer bronchopulmonaire "non a petites cellules" au moyen de profiles d'expression genique
EP1534854A4 (fr) * 2002-03-28 2006-11-15 Ohio Med College Procede et compositions pour le diagnostic et le traitement du cancer bronchopulmonaire "non a petites cellules" au moyen de profiles d'expression genique
US8722331B2 (en) 2002-03-28 2014-05-13 University Of Toledo Method for selecting a treatment for non-small cell lung cancer using gene expression profiles
US8765368B2 (en) 2007-09-17 2014-07-01 The University Of Toledo Cancer risk biomarker

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