Products for assessing colorectal cancer molecular subtype and risk of recurrence and for determining and administering treatment protocols based thereon
Inventors
Assignees
Publication Number
US-11549152-B2
Publication Date
2023-01-10
Expiration Date
2039-03-07
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Abstract
Products, systems, and methods for classifying human colorectal cancer into a consensus molecular subtype (CMS) and for assessing risk of recurrence based on CMS scores and based on risk scores derived from abbreviated gene expression profiles, for determining suitable treatment protocols for human colorectal cancer patients based on the determined CMS classification and based on the determined risk of recurrence, and for administering the suitable treatment protocols.
Core Innovation
The invention provides products, systems, and methods for classifying human colorectal cancer into consensus molecular subtypes (CMS) using abbreviated gene expression profiles, and for assessing risk of recurrence based on CMS scores or on risk scores derived from a selected set of genes. These classifications and assessments enable the determination of suitable treatment protocols specific for the patient’s colorectal cancer based on molecular subtype and recurrence risk, and guide the administration of these protocols.
The problem addressed is that conventional CMS determination methods require analyzing the expression of hundreds of genes using costly, time-consuming, and technically challenging processes—particularly microarray methods that may not be compatible with clinical tissue preservation practices such as FFPE. This hinders timely, cost-effective, and clinically practical diagnosis and treatment selection for colorectal cancer patients.
By mathematically transforming raw gene expression values from a reduced, highly-predictive subset of genes into CMS or risk scores, this invention enables accurate subtyping and risk assessment using rapid, inexpensive techniques like RT-PCR or RNA sequencing on clinical tissue samples. The system supports reporting of probabilities for each CMS subtype and recurrence likelihood, and provides recommendations for personalized treatment protocols.
Claims Coverage
The claims introduce several inventive features focused on kits comprising labelled oligonucleotides targeting specific gene sets for colorectal cancer CMS subtyping and associated reagents or implements.
Kit containing oligonucleotides for CMS subtyping by gene panel
A kit comprising 12 to 100 oligonucleotides for measuring expression of at least one gene from each of four specified gene sets (CMS1, CMS2, CMS3, CMS4), where each gene set includes enumerated ENTREZ IDs. The oligonucleotides are labeled, bound to a substrate or substrate surface, or both.
Preferred gene selection for CMS classification
Selection of at least one gene from a specified subgroup within each CMS gene set for higher predictive accuracy, including specified ENTREZ IDs for each subtype, particularly: CMS1 (MTA2, ASPHD2, TSPAN6, QPRT, CDC42), CMS2 (TP53RK, PLAGL2, POFUT1, STAU1, DUSP4), CMS3 (TIMP3, ASRGL1, SLITRK6, RETNLB, RBMS1), and CMS4 (LAYN, ZFPM2, STON1, PDLIM3, AEBP1).
Kit including substrate and reaction containers
The substrate for the oligonucleotides may comprise a plate, chip, array, grid, or flow cell, and the kit may include a reaction container such as a sample tube or reaction plate (including 96- or 384-well plates).
Inclusion of polymerase chain reaction reagents
The kit may further comprise one or more PCR reagents such as buffering agent, deoxynucleotide triphosphates, DNA polymerase, and detection reagent, with the detection reagent being a fluorescent dye or labeled probe.
Inclusion of reverse transcription reagents
The kit may further include one or more reverse transcription reagents selected from buffering agent, deoxynucleotide triphosphates, and reverse transcriptase.
The inventive features encompass kits for CMS subtyping via defined panels of gene-specific oligonucleotides, with optional reagents and physical supports designed for molecular diagnostic workflows targeting specific colorectal cancer molecular subtypes.
Stated Advantages
Provides a time- and cost-effective clinical test to determine consensus molecular subtype (CMS), microsatellite instability, and subtype-specific prognosis for colorectal cancer tumors.
Enables accurate CMS and recurrence risk determination using a reduced number of highly-predictive genes, making the process rapid, inexpensive, and suitable for routine clinical use.
Facilitates use of formalin-fixed paraffin-embedded (FFPE) tissue samples, aligning with standard clinical practice and overcoming microarray limitations.
Supports personalized cancer treatment decisions, including confirmation or modification of observation or chemotherapy protocols based on accurate CMS and risk assessments.
Eases demonstration of analytic validity, reducing cost and complexity of regulatory approval for commercial diagnostics.
Documented Applications
Classifying colorectal cancer samples into CMS1, CMS2, CMS3, CMS4, or mixed/unclassified subtype for personalized treatment selection.
Predicting risk of recurrence for colorectal cancer using abbreviated gene expression profiles.
Determining and/or administering suitable treatment protocols for colorectal cancer patients based on determined CMS classification and risk of recurrence.
Facilitating diagnostic decisions and therapeutic choices, including whether to recommend observation alone or specific chemotherapies such as FOLFIRI or cetuximab, based on molecular subtype and recurrence risk.
Clinical evaluation of responses to chemotherapy regimens (e.g., FOLFIRI, FOLFOX, cetuximab) using molecular subtyping for improved outcomes.
Use with FFPE tissue samples and integration with rapid gene expression quantitation methods such as RT-PCR or RNA sequencing for diagnostic laboratories.
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