Rare clonotypes and uses thereof
First Claim
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1. A method of selecting one or more patient-specific clonotypes correlated with a lymphoid neoplasm for monitoring a minimal residual disease thereof, the method comprising the steps of:
- (a) amplifying molecules of nucleic acid from T-cells and/or B-cells in a sample from a patient, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes;
(b) sequencing the amplified molecules of nucleic acid to form a clonotype profile containing the one or more patient-specific clonotypes;
(c) comparing nucleotide sequences of the one or more patient-specific clonotypes from the clonotype profile to nucleotide sequences of clonotypes in a clonotype database, wherein the nucleotide sequences of clonotypes in a clonotype database are from at least one individual other than the patient to determine a presence, absence and/or level in the clonotype database of each of the nucleotide sequences of the one or more patient-specific clonotypes from the clonotype profile; and
(d) selecting the one or more patient-specific clonotypes for monitoring the minimal residual disease which are each correlated with the lymphoid neoplasm and which are each absent from the clonotype database or at a level in the clonotype database that is below a predetermined frequency.
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Abstract
The invention is directed to a method of selecting disease-correlated clonotypes that have a reduced likelihood of producing a false positive signal of relapse when, used to monitor minimal residual disease. In accordance with the invention, candidate correlating clonotype are obtained from a patient, the rarity of each is determined either by comparison with a clonotype database or a clonotype model, and one or more of the rarest of such clonotypes are used to monitor the minimal residual disease.
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10 Claims
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1. A method of selecting one or more patient-specific clonotypes correlated with a lymphoid neoplasm for monitoring a minimal residual disease thereof, the method comprising the steps of:
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(a) amplifying molecules of nucleic acid from T-cells and/or B-cells in a sample from a patient, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes; (b) sequencing the amplified molecules of nucleic acid to form a clonotype profile containing the one or more patient-specific clonotypes; (c) comparing nucleotide sequences of the one or more patient-specific clonotypes from the clonotype profile to nucleotide sequences of clonotypes in a clonotype database, wherein the nucleotide sequences of clonotypes in a clonotype database are from at least one individual other than the patient to determine a presence, absence and/or level in the clonotype database of each of the nucleotide sequences of the one or more patient-specific clonotypes from the clonotype profile; and (d) selecting the one or more patient-specific clonotypes for monitoring the minimal residual disease which are each correlated with the lymphoid neoplasm and which are each absent from the clonotype database or at a level in the clonotype database that is below a predetermined frequency. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A method of selecting one or more patient-specific clonotypes correlated with a lymphoid neoplasm for monitoring a minimal residual disease thereof, the method comprising the steps of:
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(a) amplifying molecules of nucleic acid from T-cells and/or B-cells in a sample from a patient, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes; (b) sequencing the amplified molecules of nucleic acid to form a clonotype profile containing the one or more patient-specific clonotypes; (c) comparing nucleotide sequences of constituent regions of each of the one or more patient-specific clonotypes from the clonotype profile to corresponding nucleotide sequences of constituent regions of a clonotype model to determine an expected frequency of occurrence for each of the constituent regions; and (d) selecting at least one clonotype from the one or more patient-specific clonotypes for monitoring the minimal residual disease, wherein the at least one clonotype is correlated with the lymphoid neoplasm, and wherein a product of the expected frequencies of occurrence of each of the constituent regions of the at least one clonotype is below a predetermined frequency.
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Specification