Cancer diagnosis and therapy based on mutations in TGF-beta receptors
First Claim
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1. A method to aid in predicting prognosis of a cancer patient comprising determining the quantity of functional type II receptor for TGFβ
- (RII) in cells from tumor tissue of the patient, and comparing the quantity of RII in tumor cells to the quantity of RII in non-neoplastic cells of the patient, reduced RII in the tumor cells being indicative of altered prognosis.
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Abstract
This invention is based on the discovery that the type II TGFβ receptor (RII) is a cancer suppressor gene which is genetically inactivated (mutated) in approximately 25% of colon cancers, including nearly all colon cancers of the class identified as mutator/microsatellite instability/RER. Methods are provided for detecting inactivation of RII for use in cancer diagnosis or prognosis.
3 Citations
38 Claims
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1. A method to aid in predicting prognosis of a cancer patient comprising determining the quantity of functional type II receptor for TGFβ
- (RII) in cells from tumor tissue of the patient, and comparing the quantity of RII in tumor cells to the quantity of RII in non-neoplastic cells of the patient, reduced RII in the tumor cells being indicative of altered prognosis.
- View Dependent Claims (2)
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3. A method to aid in classifying tumor cell phenotype in a patient comprising determining the presence or absence of functional RII receptor for TGFβ
- in tumor tissue from the patient, the absence of functional RII being indicative of carcinoma with replication errors (RER phenotype).
- View Dependent Claims (4)
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5. A method to aid in classifying tumor cell phenotype comprising determining, in a sample containing cells or extract of cells of the tumor, presence or absence of a nucleotide sequence encoding a mutant form of TGFβ
- receptor RII, wherein the mutation is selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, the presence of the nucleotide sequence encoding a mutant form of TGFβ
receptor RII being indicative of carcinoma with replication errors (RER phenotype). - View Dependent Claims (6)
- receptor RII, wherein the mutation is selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, the presence of the nucleotide sequence encoding a mutant form of TGFβ
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7. A method to aid in diagnosing cancer in a patient comprising determining the presence or absence of functional RII receptor for TGFβ
- in tissue from the patient, the absence of functional RII being indicative of tumor tissue or precancerous lesions in the patient.
- View Dependent Claims (8, 9)
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10. A screening method to aid in diagnosing genetic susceptibility to cancer in a patient comprising determining the presence or absence of mutant forms of RII receptor for TGFβ
- in a sample from the patient, the presence of mutant forms of RII being indicative of precancerous lesions in the patient.
- View Dependent Claims (11, 12, 13, 16, 17, 18, 19)
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14. An assay for expression in cells of mutant type II receptor for TGFβ
- (RII) comprising determining, in a sample containing cells or cell extracts, presence or absence of a nucleotide sequence encoding a mutant form of TGFβ
receptor RII, wherein the mutation is selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence.
- (RII) comprising determining, in a sample containing cells or cell extracts, presence or absence of a nucleotide sequence encoding a mutant form of TGFβ
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15. A heterologous polynucleotide comprising a nucleotide sequence encoding a mutant form of TGFβ
- receptor RII, wherein the mutation is selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence.
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20. A mutant protein of human TGFβ
- receptor RII substantially free of other human proteins, the mutant RII protein having a sequence encoded by RII cDNA altered by a mutation selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence.
- View Dependent Claims (21, 22, 23, 24, 25, 26, 30, 31)
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27. A therapeutic method for treating a colon cancer patient, wherein neoplastic cells of the patient express a mutant form of RII, the mutation being selected from the group consisting of a two base pair insertion of GT which occurs in a six base pair repeat sequence GTGTGT at codons 1931-1936 of the normal RII sequence, deletion of one A base pair from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, and deletion of two A base pairs from a ten base pair poly A sequence at codons 709 to 718 of the normal RII sequence, comprising administering to the patient an effective amount of specific activated cytotoxic immune cells, wherein the activated immune cells are specifically immunoreactive with the mutant form of RII expressed by the neoplastic cells of the patient.
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28. A therapeutic method for treating a patient having colon cancer of the RER phenotype comprising administering to the patient a gene therapy vector encoding functional TGFβ
- receptor RII operably linked to a promoter, wherein said gene therapy vector is expressed in the patient to produce functional RII.
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29. A method to aid in diagnosing cancer in a patient comprising detecting a mutant RII receptor for TGFβ
- in a sample of biological fluid from the patient.
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32. A method to aid in diagnosing cancer in a patient comprising detecting, in the patient, a non-functional mutant form of a growth regulatory gene, wherein the growth regulatory gene encodes a type II receptor which is a member of a family of serine/threonine receptors which bind members of a family of TGFβ
- -like factors or the growth regulatory gene contains repetitive DNA sequence motifs in the wild-type coding region, presence of the non-functional mutant form of the growth-regulatory gene being indicative of tumor tissue or precancerous lesions in the patient.
- View Dependent Claims (33, 34)
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35. A therapeutic method for treating a cancer patient, wherein neoplastic cells of the patient express a non-functional mutant form of a growth regulatory gene, wherein the growth regulatory gene encodes a type II receptor which is a member of a family of serine/threonine receptors which bind members of a family of TGFβ
- -like factors or the growth regulatory gene contains repetitive DNA sequence motifs in the wild-type coding region, comprising administering to the patient an immunogenic amount of an immunogenic composition comprising the non-functional mutant for of the growth regulatory gene product or an expression vector encoding the same non-functional mutant form of the growth regulatory gene as the neoplastic cells of the patient.
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36. A therapeutic method for treating a cancer patient, wherein neoplastic cells of the patient express a non-functional mutant form of a growth regulatory gene, wherein the growth regulatory gene encodes a type II receptor which is a member of a family of serine/threonine receptors which bind members of a family of TGFβ
- -like factors or the growth regulatory gene contains repetitive DNA sequence motifs in the wild-type coding region, comprising administering to the patient an effective amount of an antibody, the antibody being specifically immunoreactive with the non-functional mutant form of the growth regulatory gene expressed by the neoplastic cells of the patient.
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37. A therapeutic method for treating a cancer patient, wherein neoplastic cells of the patient express a non-functional mutant form of a growth regulatory gene, wherein the growth regulatory gene encodes a type II receptor which is a member of a family of serine/threonine receptors which bind members of a family of TGFβ
- -like factors or the growth regulatory gene contains repetitive DNA sequence motifs in the wild-type coding region, comprising administering to the patient an effective amount of specific activated cytotoxic immune cells, wherein the activated immune cells are specifically immunoreactive with the non-functional mutant form of the growth regulatory gene expressed by the neoplastic cells of the patient.
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38. A therapeutic method for treating a cancer patient, wherein neoplastic cells of the patient express a non-functional mutant form of a growth regulatory gene, wherein the growth regulatory gene encodes a type II receptor which is a member of a family of serine/threonine receptors which bind members of a family of TGF-like factors or the growth regulatory gene contains repetitive DNA sequence motifs in the wild-type coding region, comprising administering to the patient a gene therapy vector encoding a functional form of the growth regulatory gene expressed by the neoplastic cells of the patient,the gene being operably linked to a promoter, wherein said gene therapy vector is expressed in the patient to produce a functional form of the growth regulatory gene expressed by the neoplastic cells of the patient.
Specification