Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-12-17
2003-10-21
Martinell, James (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023500, C435S325000, C435S091200, C435S252300, C435S006120
Reexamination Certificate
active
06635748
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to methods for predicting the behavior of tumors and in particular, but not exclusively, to methods in which a tumor sample is examined for expression of a specified gene sequence which indicates propensity for metastatic spread.
BACKGROUND OF THE INVENTION
Despite use of a number of histochemical, genetic, and immunological markers, clinicians still have a difficult time predicting which tumors will metastasize to other organs. Some patients are in need of adjuvant therapy to prevent recurrence and metastasis and others are not. Distinguishing between these subpopulations of patients is not straightforward. Thus the course of treatment is not easily charted. There is therefore a need in the art for new markers for distinguishing between tumors of differing metastatic potential.
SUMMARY OF THE INVENTION
It is an object of the invention to provide reagents and methods for determining which tumors are likely to metastasize and for suppressing metastases of these tumors. These and other objects of the invention are provided by one or more of the embodiments described below.
One embodiment of the invention is an isolated and purified protein having an amino acid sequence which is at least 85% identical to an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.
Another embodiment of the invention is an isolated and purified polypeptide which consists of at least 8 contiguous amino acids of a protein having an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Yet another embodiment of the invention is a fusion protein which comprises a first protein segment and a second protein segment fused to each other by means of a peptide bond. The first protein segment consists of at least 8 contiguous amino acids selected from an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Still another embodiment of the invention is a preparation of antibodies which specifically bind to a protein with an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Even another embodiment of the invention is a cDNA molecule which encodes an isolated and purified protein having an amino acid sequence which is at least 85% identical to an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO:1-18. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.
Another embodiment of the invention is a cDNA molecule which encodes at least 8 contiguous amino acids of a protein encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Even another embodiment of the invention is a cDNA molecule comprising at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Still another embodiment of the invention is a cDNA molecule which is at least 85% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.
A further embodiment of the invention is an isolated and purified subgenomic polynucleotide comprising a nucleotide segment which hybridizes to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18 after washing with 0.2×SSC at 65° C.
Another embodiment of the invention is a construct comprising a promoter and a polynucleotide segment encoding at least 8 contiguous amino acids of a protein encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18. The polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter.
Yet another embodiment of the invention is a host cell comprising a construct which comprises a promoter and a polynucleotide segment encoding at least 8 contiguous amino acids of a protein encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
Even another embodiment of the invention is a recombinant host cell comprising a new transcription initiation unit. The new transcription initiation unit comprises in 5′ to 3′ order (a) an exogenous regulatory sequence, (b) an exogenous exon, and (c) a splice donor site. The new transcription initiation unit is located upstream of a coding sequence of a gene. The coding sequence comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18. The exogenous regulatory sequence controls transcription of the coding sequence of the gene.
Still another embodiment of the invention is a polynucleotide probe comprising (a) at least 12 contiguous nucleotides selected from the group consisting of SEQ ID NOS:1-18 and (b) a detectable label.
Even another embodiment of the invention is a method for identifying a metastatic tissue or metastatic potential of a tissue. An expression product of a gene comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-4, 6-13, and 15-18 is measured in a tissue sample. A tissue sample which expresses a product of a gene comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 4, 11, 16, 17, and 18 or which does not express a product of a gene comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:2, 3, 6, 7, 8, 9, 10, 12, 13, and 15 is identified as metastatic or as having metastatic potential.
Still another embodiment of the invention is a method of screening test compounds for the ability to suppress the metastatic potential of a tumor. A biological sample is contacted with a test compound. Synthesis of a protein having an amino acid sequence encoded by a polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-4, 6-13, and 15-18 is measured in the biological sample. A test compound which decreases synthesis of a protein encoded by a polynucleotide comprising SEQ ID NOS:1, 4, 11, 16, 17, or 18 or which increases synthesis of a protein encoded by a polynucleotide comprising SEQ ID NOS:2, 3, 6, 7, 8, 9, 10, 12, 13, or 15 is identified as a potential agent for suppressing the metastatic potential of a tumor.
Another embodiment of the invention is a method of predicting propensity for high-grade or low-grade metastatic spread of a colon tumor. An expression product of a gene having a sequence selected from the group consisting of SEQ ID NO:16 and 17 is measured in a colon tumor sample. A colon tumor sample which expresses the product of SEQ ID NO:16 is categorized as having a high propensity to metastasize and a colon tumor sample which expresses the product of SEQ ID NO:17 is categorized as having a low propensity to metastasize.
Still another embodiment of the invention is a set of primers for amplifying at least a portion of a gene having a coding sequence selected from the group consisting of the nucleotide sequences shown in SEQ ID NOS:1-18.
Even another embodiment of the invention is a polynucleotide array comprising at least one single-stranded polynucleotide which comprises at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1-18.
A further embodiment of the invention is a method of identifying a metastatic tissue or metastatic potential of a tissue. A tissue sample c
Giese Klaus
Xin Hong
Chiron Corporation
Martinell James
Potter Jane E. R.
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