Compositions and methods for classifying thyroid nodule disease
Inventors
Davicioni, Elai • Wiseman, Sam Michael
Assignees
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Publication Number
US-10422009-B2
Publication Date
2019-09-24
Expiration Date
Abstract
A system for classifying thyroid nodule tissue as malignant or benign is provided that is based on the identification of sets of gene transcripts, which are characterized in that changes in expression of each gene transcript within a set of gene transcripts can be correlated to with either malignant or benign thyroid nodule disease. The thyroid classification system provides for sets of “thyroid classifying” target sequences and further provides for combinations of polynucleotide probes and primers derived there from. These combinations of polynucleotide probes can be provided in solution or as an array. The combination of probes and the arrays can be used for diagnosis. The invention further provides further methods of classifying thyroid nodule tissue.
Core Innovation
The invention provides an expression-based diagnostic method for thyroid condition classification using reference transcript expression levels derived from SEQ ID No. 1 to 584. A test sample from a subject’s thyroid is first identified as indeterminate by cytological evaluation, and an expression level is assayed for two transcript groups comprising a first group and a second group of transcripts. The first group and the second group are distinguished by transcript-sequence homology relationships to sequences as set forth in SEQ ID No. 1-6, 11-13, 16-248, and SEQ ID No. 7-10, 14, 15, 249-584, respectively.
Probes selected for at least two sequences in each group are used to assay expression levels by sequencing, array hybridization, or nucleic acid amplification. In a programmed computer, the assayed expression levels are compared to reference expression levels of transcripts corresponding to sequences set forth in SEQ ID No. 1 to 584. Malignant classification is assigned when there is an increase in expression level corresponding to the first group or a decrease in expression level corresponding to the second group.
Benign classification is assigned when there is an increase in expression level corresponding to the second group or a decrease in expression level corresponding to the first group. The approach uses group-wise directionality of expression changes between the first group and second group to classify indeterminate thyroid samples as malignant or benign for a thyroid condition, based on comparison to reference expression levels corresponding to the SEQ ID transcript set.
Claims Coverage
The independent claim explicitly covers a programmed-computer method that classifies indeterminate thyroid cytology samples as malignant or benign by assaying expression levels for two transcript groups and comparing group-level expression patterns to reference expression levels from SEQ ID No. 1 to 584. The inventive features center on two group-defined transcript sets based on sequence homology and a decision rule based on increases or decreases in the two transcript groups for malignant versus benign classification.
Two-group transcript expression classification for indeterminate thyroid cytology
Assaying an expression level of a first group of transcripts and a second group of transcripts in a test sample from a thyroid of a subject identified as indeterminate by cytological evaluation, and in a programmed computer comparing the expression levels to reference expression levels corresponding to sequences set forth in SEQ ID No. 1 to 584 to classify the sample as malignant or benign based on expression increases and decreases in the two groups.
Sequence homology-constrained transcript groups with selected probes
The first group includes at least two transcripts having at least about 90% sequence homology to at least two sequences selected from SEQ ID No. 1-6, 11-13, and 16-248, and the second group includes at least two transcripts having at least about 90% sequence homology to at least two sequences selected from SEQ ID No. 7-10, 14, 15, and 249-584, wherein the assaying comprises use of probes selected for the at least two sequences.
Malignant classification via increased first-group or decreased second-group expression
Classifying the test sample as malignant for a thyroid condition if there is an increase in an expression level corresponding to the first group of transcripts or a decrease in an expression level corresponding to the second group of transcripts.
Benign classification via increased second-group or decreased first-group expression
Classifying the test sample as benign for a thyroid condition if there is an increase in an expression level corresponding to the second group of transcripts or a decrease in an expression level corresponding to the first group of transcripts.
Overall claim coverage focuses on a two-transcript-group, sequence-homology-constrained expression assay for cytologically indeterminate thyroid samples, with malignant/benign assignment determined by whether expression changes show increased first-group or decreased second-group expression, or increased second-group or decreased first-group expression, after comparison to reference expression levels for SEQ ID No. 1 to 584.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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