Method of diagnosing poor survival prognosis colon cancer using microRNA-21
Inventors
Croce, Carlo M. • Harris, Curtis C. • Schetter, Aaron J.
Assignees
US Department of Health and Human Services • Office of Technology Transfer • Ohio State University Research Foundation
Publication Number
US-8084199-B2
Publication Date
2011-12-27
Expiration Date
2027-07-12
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Abstract
The present invention provides novel methods and compositions for the diagnosis and treatment of colon cancers. The invention also provides methods of identifying inhibitors of tumorigenesis.
Core Innovation
The invention provides novel methods and compositions for diagnosing and treating colon cancers, particularly focusing on methods to identify patients with poor survival prognosis colon adenocarcinoma. This is achieved by measuring the levels of specific microRNA (miR) gene products in test samples from subjects, comparing these levels to control samples, wherein altered levels indicate the presence, risk, or prognosis of colon cancer-related diseases.
Colon adenocarcinoma is a major cause of cancer mortality worldwide and is the third most common and second leading cause of cancer death in the United States. Despite modest declines in 5-year mortality rates, there is a strong need to identify new prognostic biomarkers and therapeutic targets. Surgery remains the only curative treatment, with chemotherapy providing limited therapeutic value. The problem addressed by the invention is the lack of reliable, clinically relevant biomarkers that are easy to measure and strongly associated with clinical outcomes, which would aid in diagnosis, prognosis, and treatment decisions in colon cancer, particularly adenocarcinoma.
MicroRNAs, small 18-25 nucleotide non-coding RNA molecules regulating translation, have altered expression in most tumor types, including colon tumors. Their expression patterns are associated with cancer progression and prognosis. The invention leverages this by focusing on specific microRNAs, especially miR-21 and others like miR-20a, miR-106a, miR-181b, and miR-203, whose altered expression levels in subject samples are indicative of cancer presence and prognosis. Additionally, the invention provides methods for inhibiting tumorigenesis by modulating miR gene product levels via administration of miR gene products or compounds inhibiting their expression, and for identifying inhibitors of tumorigenesis by assessing changes in miR levels upon compound treatment.
Claims Coverage
The patent presents three main inventive features related to diagnostic and prognostic methods for colon adenocarcinoma, focusing primarily on miR-21 gene product level measurement in patient samples, comparative analysis with controls, and hybridization-based detection techniques.
Diagnosis of poor survival prognosis colon adenocarcinoma by miR-21 level measurement
The method involves measuring the level of at least one miR-21 gene product in a test sample from a subject diagnosed with colon adenocarcinoma. An increase in the miR-21 level relative to a control sample indicates poor survival prognosis colon adenocarcinoma.
Testing poor survival prognosis colon adenocarcinoma by comparative expression analysis
The method includes determining the expression level of at least one marker comprising at least one miR-21 gene product in a sample from a subject with colon adenocarcinoma, comparing it to a control from a healthy subject, and judging poor survival prognosis if the expression in the test subject is higher.
Diagnosing poor survival prognosis colon adenocarcinoma using microarray hybridization
This method comprises reverse transcribing RNA from a test sample to generate target oligodeoxynucleotides, hybridizing these to a microarray with miR-21 specific probe oligonucleotides to obtain a hybridization profile, and comparing it to a control sample's profile. An increased signal of miR-21 relative to the control indicates poor survival prognosis colon adenocarcinoma.
The claims focus on diagnostic and prognostic methods for colon adenocarcinoma utilizing the detection and quantification of miR-21 gene product levels in various sample types through direct measurement and microarray hybridization techniques. They describe comparing these levels to controls to assess poor survival prognosis, thereby encompassing methods for cancer diagnosis and prognosis based on miR-21 expression.
Stated Advantages
The invention provides a novel prognostic biomarker (miR-21) for colon adenocarcinoma, which is strongly associated with clinical outcomes including survival prognosis independent of traditional clinical covariates.
It enables prediction of poor response to adjuvant chemotherapy, thereby aiding in treatment decisions.
The methods allow for early diagnosis, risk assessment, and monitoring of colon cancer by measuring microRNA levels, providing systematic and reproducible biomarkers linked to tumor progression.
The use of microRNA markers offers potential therapeutic targets with approaches to inhibit tumorigenesis via modulation of miR gene product levels.
Documented Applications
Diagnosis and risk assessment of colon cancer-related diseases, including detection of colon adenocarcinoma and determining survival prognosis by measuring miR-21 and other miR gene products in patient tissue or bodily fluid samples.
Predicting patient response to adjuvant chemotherapy in colon cancer by assessing miR-21 expression levels.
Therapeutic intervention methods involving administration of isolated miR gene products or compounds inhibiting their expression to inhibit tumorigenesis in colon cancer patients.
Methods for identifying inhibitors of tumorigenesis by evaluating changes in miR gene product expression levels in cells exposed to test agents.
Use of microRNA expression profiles and signatures to classify tumor type, stage, and prognosis, enabling precision medicine approaches including personalized therapy selection and monitoring of treatment efficacy.
Development and use of animal models with altered expression of specific miR gene products for studying colon cancer pathogenesis and screening therapeutic agents.
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