Assessing colorectal cancer molecular subtype and uses thereof
Inventors
Assignees
Publication Number
US-11851713-B2
Publication Date
2023-12-26
Expiration Date
2039-03-07
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Abstract
Disclosed are genetic methods and tools for colon cancer disease classification in disease subtypes, CMS1, CMS2, CMS3, CMS4, as well as improved methods for rapid, more accurate, and more reliably reproducible disease subtype determination. Tailored treatment protocols are also provided, employing the predicted CMS of the subject sample. Genetic sequence binding targets for some or all of these gene panels may be affixed to a solid substrate, and included as part of a screening tool and/or diagnostic kit. The expression levels of the genes may be assessed to provide a genetic signature for a subtype or lack of subtype (CMS1, CMS2, CMS3, CMS4, combination subtype). The methods employ a scoring system, wherein a score is derived from the genetic expression profile/signature of the panel of selected genes, and a qualifying continuous score for each CMS subtype is determined against a predictive threshold for each colon cancer subtype.
Core Innovation
The disclosed invention provides methods and products for determining the consensus molecular subtype (CMS) of colorectal cancer using a reduced gene panel. The methodology shifts from measuring hundreds of genes—required by earlier CMS classification techniques—to as few as three highly-predictive genes per CMS subtype. By quantifying the expression levels of at least three genes from four specific gene sets, each correlating with one CMS subtype (CMS1, CMS2, CMS3, CMS4), a gene expression signature is derived from a colorectal tissue sample. The invention introduces a scoring system that calculates a continuous CMS score for each subtype, which is then compared to predictive thresholds to assign the sample to the most probable CMS.
The need addressed stems from limitations in conventional CMS determination, where existing methods use large gene sets and expensive, labor-intensive microarray platforms, often requiring fresh-frozen tumor samples. These approaches introduce major hurdles for clinical implementation, particularly since most clinical practice relies on formalin-fixed paraffin-embedded (FFPE) tissue. The disclosed methods simplify and accelerate the subtype determination process, allowing it to be performed on FFPE samples using rapid and cost-effective detection means such as RT-PCR or RNA sequencing.
Furthermore, the continuous scoring and ranking approach provides more reproducible and reliable subtype assignments compared to previous methods. This improved accuracy directly impacts clinical decision-making, enabling patient-specific, CMS-guided treatment protocol recommendations. The invention extends to include gene panels, kits, and computer-implemented systems for both CMS determination and guiding therapy selection, such as recommending or withholding chemotherapeutic agents based on the result. The scoring approach is also stated to facilitate regulatory approval due to the manageable number of assessed genes.
Claims Coverage
There are three independent inventive features articulated in the claims.
Continuous score method for CMS classification using reduced gene panels
A method is disclosed for determining the predicted consensus molecular subtype (CMS) of colon cancer by: 1. Contacting a genetic sample with a plurality of genetic sequence binding targets and measuring the expression levels of at least three genes from each of four specific gene sets, each set corresponding to a different CMS subtype (CMS1, CMS2, CMS3, CMS4). 2. Calculating a gene expression signature value using the measured expression levels for each subset. 3. Comparing each signature value to a predicted threshold to generate a continuous CMS score for each subtype. 4. Selecting and ranking the qualifying CMS scores that exceed their thresholds, then assigning the CMS with the highest ranked score to the sample. This method enables subtype classification with improved reproducibility relative to methods not employing continuous scoring.
Gene screening panel for CMS molecular subtyping
A gene screening panel is provided consisting of genetic sequence binding targets for four gene sets, each set containing at least three genes specific to one of the CMS subtypes: - CMS1: AXIN2, SEMA5A, CDHR1, CTTNBP2, WARS, HPSE, ATP9A, GNLY, DACH1, EMP2AIP1 - CMS2: POFUT1, QPRT, PLAGL2, CEL, TRIB2, DDX27, DUSP4, FSCN1, OSER1, LYZ - CMS3: TIMP3, CAPN9, VAV2, FCGBP, FBN1, IGFBP5, SPINK4, REG4, CEBPB, CLCA1 - CMS4: MGP, AOC3, TINS1, CCDC80, SPOCK1, LMOD1, PLN, AKAP12, FERMT2, HSPB8 The binding targets may be affixed to a solid surface and can include polynucleotides, proteins, peptides, or peptide nucleic acids. This gene screening panel enables CMS determination from human tissue samples.
Method for providing an enhanced treatment plan based on CMS prediction
A method is provided for delivering an enhanced treatment plan to a subject based on a predicted CMS determined by the above-described continuous score method. The method comprises: - Identifying the presence or absence of colon cancer from a genetic sample and determining the sample's CMS. - Providing an enhanced treatment plan specific to the predicted CMS subtype. For example, the plan may recommend absence or inclusion of chemotherapeutic agents depending on whether CMS4 (or a combination CMS comprising CMS4) is present, versus CMS1, CMS2, or CMS3. - Further, the treatment plan can consider mutation analysis of select genes (e.g., KRAS, NRAS, BRAF, EGFR, ERBB2, UGT1A1) as an additional stratification factor.
The inventive features collectively enable a clinically practical genetic approach to colorectal cancer CMS subtyping, streamlined test panels and kits, and tailored therapeutic plans based on an abbreviated gene expression and scoring system.
Stated Advantages
Enables rapid, cost-effective, and clinically feasible CMS determination using a reduced number of predictive genes rather than hundreds required by prior methods.
Permits testing on formalin-fixed paraffin-embedded (FFPE) tissue samples, aligning with standard clinical practice and avoiding the need for fresh-frozen tissue.
Improves reproducibility and reliability of colorectal cancer subtype classification through the use of continuous scoring and ranked thresholds.
Facilitates more personalized and informed treatment decision-making by directly connecting subtype determination to tailored treatment protocols.
Reduces unnecessary exposure to chemotherapy and associated toxic effects in patients unlikely to benefit, thereby lowering overall treatment costs and side effects.
Satisfies regulatory requirements more easily due to the manageable gene panel size, supporting demonstration of analytic validity for diagnostic approval.
Documented Applications
Determining the consensus molecular subtype (CMS1, CMS2, CMS3, CMS4, or mixed/unclassified) of colorectal cancer using gene expression profiling of reduced gene panels.
Guiding and selecting tailored colorectal cancer treatment protocols specific to the CMS subtype, including recommendations for, or omission of, chemotherapeutic agents.
Identifying high- or low-risk of recurrence scores in colorectal cancer patients, particularly in stage II disease, to inform observation versus chemotherapy decisions.
Predicting response to specific treatments, such as cetuximab or FOLFIRI, based on CMS subtype and associated score, for metastatic colorectal cancer patients.
Providing diagnostic kits and gene panels for clinical laboratories or healthcare providers enabling rapid CMS testing from patient tissue samples.
Generating clinician reports and user interface outputs that display CMS scores, subtype predictions, and associated treatment recommendations.
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