Chemistry: analytical and immunological testing – Thyroid hormone tests
Reexamination Certificate
1999-03-15
2001-11-13
Brusca, John S. (Department: 1631)
Chemistry: analytical and immunological testing
Thyroid hormone tests
C435S006120, C435S007100, C435S069100, C530S387100
Reexamination Certificate
active
06316272
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the identification of expression profiles and the nucleic acids involved in colorectal cancer, and to the use of such expression profiles and nucleic acids in diagnosis and prognosis of colorectal cancer. The invention further relates to methods for identifying candidate agents which modulate colorectal cancer.
BACKGROUND OF THE INVENTION
Colorectal cancer is a significant cancer in Western populations. It develops as the result of a pathologic transformation of normal colon epithelium to an invasive cancer. There have been a number of recently characterized genetic alterations that have been implicated in colorectal cancer, including mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, with recent work suggesting that mutations in DNA repair genes may also be involved in tumorigenesis.
For example, inactivating mutations of both alleles of the adenomatous polyposis coli (APC) gene, a tumor suppressor gene, appears to be one of the earliest events in colorectal cancer, and may even be the initiating event. Other genes implicated in colorectal cancer include the MCC gene, the p53 gene, the DCC (deleted in colorectal carcinoma) gene and other chromosome 18q genes, and genes in the TGF-&bgr; signalling pathway. For a review, see Molecular Biology of Colorectal Cancer, pp238-299, in Curr. Probi. Cancer, September/October 1997.
Imaging of colorectal cancer for diagnosis has been problematic and limited. In addition, dissemination of tumor cells (metastases) to locoregional lymph nodes is an important prognostic factor; five year survival rates drop from 80 percent in patients with no lymph node metastases to 45 to 50 percent in those patients who do have lymph node metastases. A recent report showed that micrometastases can be detected from lymph nodes using reverse transcriptase-PCR methods based on the presence of mRNA for carcinoembryonic antigen, which has previously been shown to be present in the vast majority of colorectal cancers but not in normal tissues. Liefers et al., New England J. of Med. 339(4):223 (1998).
Thus, methods that can be used for diagnosis and prognosis of colorectal cancer would be desirable.
Accordingly, it is an object of the invention to provide methods that can be used in diagnosis and prognosis of colorectal cancer. It is a further object to provide methods that can be used to screen candidate bioactive agents for the ability to modulate colorectal cancer. Additionally, it is an object to provide molecular targets for therapeutic intervention in colorectal and other cancers.
SUMMARY OF THE INVENTION
In accordance with the objects outlined above, the present invention provides novel methods for diagnosis and prognosis evaluation for colorectal cancer (CRC), as well as methods for screening for compositions which modulate CRC. In one aspect, a method of screening drug candidates comprises providing a cell that expresses an expression profile gene selected from the group consisting of the expression profile genes set forth in Tables 1, 2, 3, 4, 5, 6 and 7. The method further includes adding a drug candidate to said cell and determining the effect of said drug candidate on the expression of said expression profile gene.
In one embodiment, the method of screening drug candidates includes comparing the level of expression in the absence of said drug candidate to the level of expression in the presence of said drug candidate, wherein the concentration of said drug candidate can vary when present, and wherein said comparison can occur after addition or removal of the drug candidate. In a preferred embodiment, the cell expresses at least two expression profile genes. The profile genes may show an increase or decrease.
Also provided herein is a method of screening for a bioactive agent capable of binding to a colorectal cancer modulator protein (CCMP), said method comprising combining said CCMP and a candidate bioactive agent, and determining the binding of said candidate agent to said CCMP. Preferably the CCMP is a product encoded by a gene set forth in Tables 1-7.
Further provided herein is a method for screening for a bioactive agent capable of modulating the activity of a CCMP, said method comprising combining said CCMP and a candidate bioactive agent, and determining the effect of said candidate agent on the bioactivity of said CCMP. Preferably the CCMP is a product encoded by a gene set forth in Tables 1-7.
Additionally, provided herein is a method of evaluating the effect of a candidate colorectal cancer drug comprising administering said drug to a patient, removing a cell sample from said patient; and determining the expression profile of said cell. This method may further comprise comparing said expression profile to an expression profile of a healthy individual. In a preferred embodiment, said expression profile includes at least two genes selected from the group consisting of those set forth in Tables 1-7.
Moreover, provided herein is a biochip comprising a nucleic acid segment selected from the group consisting of the sequences set forth in Tables 1-7, wherein said biochip comprises fewer than 1000 nucleic acid probes. Preferable at least two nucleic acid segments are included.
In another aspect, a method of cloning a full length gene comprising using a nucleic acid segment selected from the group consisting of the sequences set forth in Tables 1-7 to clone the full length gene.
Furthermore, a method of diagnosing colorectal cancer is provided. Said method comprises determining the expression of a gene selected from the group consisting of set forth in Tables 1-7 in a first tissue type of a first individual; and comparing said distribution to the expression of said gene from a second normal tissue type from said first individual or a second unaffected individual. A difference in said expression indicates that the first individual has colorectal cancer.
Other aspects of the invention will become apparent to the skilled artisan by the following description of the invention.
Table 1 provides the Accession numbers for genes, including expression sequence tags, (incorporated in their entirety here and throughout the application where Accession numbers are provided), upregulated in tumor tissue compared to normal colon tissue. These include Accession number U30246 (SEQ ID No. 1).
Table 2 provides the Accession numbers for genes, including expression sequence tags, upregulated in tumor tissue compared to normal colon tissue.
Table 3 provides the Accession numbers for genes, including expression sequence tags, upregulated in tumor tissue compared to normal colon tissue.
Table 4 provides the Accession numbers for genes, including expression sequence tags, upregulated in tumor tissue compared to normal colon tissue.
Table 5 provides the Accession numbers for genes, including expression sequence tags, downregulated in tumor tissue compared to normal colon tissue.
Table 6 provides the Accession numbers for genes, including expression sequence tags, downregulated in tumor tissue compared to normal colon tissue.
Table 7 provides the Accession numbers for genes, including expression sequence tags, downregulated in tumor tissue compared to normal colon tissue.
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Gish Kurt C.
Mack David
Wilson Keith E.
Brusca John S.
EOS Biotechnology, Inc.
Flehr Hohbach Test Albritton & Herbert LLP
Kim Young
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