Rare clonotypes and uses thereof
AssigneeSequenta, Inc.
InventorsFrancois Pepin, Malek Faham, Martin Moorhead
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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 clonotypes 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.
Claims24
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) obtaining a diagnostic sample from the patient comprising T-cells and/or B-cells;
- (b) amplifying molecules of nucleic acid from the T-cells and/or B-cells of the sample, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes;
- (c) sequencing the amplified molecules of nucleic acid to form a clonotype profile;
- (d) selecting a set of one or more candidate clonotypes based on their frequency in the clonotype profile;
- (e) comparing the one or more candidate clonotypes from the set to clonotypes of a clonotype database containing clonotypes from at least one individual other than the patient to determine a presence, absence and/or level in the clonotype database of each candidate clonotype and removing from the set any candidate clonotype having a frequency in the clonotype database greater than a predetermined frequency;
- and
- (f) selecting as the one or more patient-specific clonotypes for monitoring the minimal residual disease the candidate clonotypes remaining in the set.
A method for determining whether a tissue sample comprising T cells and/or B cells from a first individual contaminates a tissue sample comprising T cells and/or B cells from a second individual, the method comprising the steps of:
- generating a first clonotype profile from nucleic acid of the tissue sample from the first individual;
- generating a second clonotype profile from nucleic acid of the tissue sample from the second individual;
- comparing clonotypes from the first and second clonotype profiles to clonotypes of a clonotype database containing clonotypes from at least one individual other than the first and second individual to determine a presence, absence and/or level in the clonotype database of each clonotype from the first and second clonotype profiles which are each absent from the clonotype database or at a level in the clonotype database below a predetermined threshold;
- and
- classifying the tissue sample from the first individual as contaminated by nucleic acids from the second individual whenever any of such determined clonotypes are present in both the first and second clonotype profiles.
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) obtaining a diagnostic sample from the patient comprising T-cells and/or B-cells;
- (b) amplifying molecules of nucleic acid from the T-cells and/or B-cells of the sample, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes;
- (c) sequencing the amplified molecules of nucleic acid to form a clonotype profile;
- (d) selecting a set of candidate clonotypes, each of whose frequency in the clonotype profile exceeds a predetermined diagnostic frequency;
- (e) comparing constituent regions of each candidate clonotype of the set to corresponding regions of a clonotype model to determine expected frequencies of occurrence for each constituent region;
- and
- (f) selecting from the set candidate clonotypes as the one or more patient-specific clonotypes for monitoring the minimal residual disease whose product of frequencies of occurrence are below a predetermined frequency.
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) obtaining a diagnostic sample from the patient comprising T-cells and/or B-cells;
- (b) amplifying molecules of nucleic acid from the T-cells and/or B-cells of the sample, the molecules of nucleic acid comprising recombined DNA sequences from T-cell receptor genes or immunoglobulin genes;
- (c) sequencing the amplified molecules of nucleic acid to form a clonotype profile;
- (d) selecting a set of one or more candidate clonotypes based on their frequency in the clonotype profile;
- (e) comparing the one or more candidate clonotypes from the set to clonotypes of a clonotype database containing clonotypes from at least one individual other than the patient to determine a sequence difference between each candidate clonotype and each clonotype of the clonotype database and removing from the set any candidate clonotype having a sequence difference less than a predetermined difference;
- and
- (f) selecting as the one or more patient-specific clonotypes for monitoring the minimal residual disease the candidate clonotypes remaining in the set.
Dependencies are inferred from the claim text.