Biomarker combinations for colorectal tumors
Inventors
Therianos, Stavros • Ruegg, Curzio • Monnier-Benoit, Sylvain • Ciarloni, Laura • Hosseinian, Sahar
Assignees
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Publication Number
US-10246748-B2
Publication Date
2019-04-02
Expiration Date
Abstract
The present invention relates to methods and kits for the detection of predetermined biomarkers for early diagnosis and management of cancer, and in particular, colorectal tumors.
Core Innovation
The invention relates to peripheral blood mononuclear cells (PBMC) and blood cells biomarker panel(s) for colorectal tumor screening and prediction by measuring biomarker mRNA levels. The biomarker mRNA panel includes IL1B and PTGS2 and further includes at least one of S100A8, LTF, CXCL10, and CACNB4. The biomarker panel consists of from 3 to 29 biomarkers and does not comprise measuring more than 29 biomarkers.
The measured mRNA amounts are used to compute a probability or score, including logistic regression and penalized logistic regression. In at least one described approach, deltaCp values (Cp target minus Cp reference) from RT-qPCR are used within a model equation to generate the probability score. A thresholded score is used to rule out or rule in colorectal tumor.
The document further describes biomarker prioritization into core biomarkers (IL1B and PTGS2) and high-priority biomarkers, with optional expansion to additional high-priority biomarkers. Performance rationale is provided using ROC/AUC and related measures including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and modeling results are presented for colorectal cancer (CRC) and adenoma detection.
Claims Coverage
The partial content provided includes two independent method claims (clm-00001 and clm-00015). Across these independent claims, there are two main inventive feature groupings: a specific IL1B/PTGS2 biomarker mRNA measurement panel design (with defined optional biomarkers and a 3-to-29 biomarker limit) and, in the second independent claim, a defined subject selection constraint (age and absence of a prior colorectal tumor diagnosis/identification).
Peripheral blood RNA extraction and mRNA measurement for IL1B, PTGS2, and at least one defined additional biomarker in a 3-to-29 panel
A method comprising extracting RNA from blood cells in peripheral blood from a selected subject to produce extracted RNA, and measuring in the extracted RNA the amount of mRNA for each biomarker in one biomarker panel, wherein the biomarker panel consists of from 3 to 29 biomarkers comprising IL1B, PTGS2, and at least one of S100A8, LTF, CXCL10, and CACNB4, wherein the method does not comprise measuring more than 29 biomarkers.
Subject selection constraint for peripheral blood RNA extraction and mRNA measurement using the IL1B, PTGS2 and defined additional biomarker panel
A method comprising extracting RNA from blood cells in peripheral blood from a selected subject to produce extracted RNA, and measuring in the extracted RNA the amount of mRNA for each biomarker in a biomarker panel comprising IL1B, PTGS2, and at least one of S100A8, LTF, CXCL10, and CACNB4, wherein the subject is at least 50 years old and has not been previously diagnosed or identified as having a colorectal tumor, wherein the method does not comprise measuring more than 29 biomarkers.
The independent claims define (i) a peripheral blood RNA-based measurement method for IL1B, PTGS2, and at least one of S100A8, LTF, CXCL10, or CACNB4 using a single biomarker panel limited to 3–29 biomarkers, and (ii) for one independent claim, an additional subject-selection requirement of age and no prior colorectal tumor diagnosis/identification.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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