Colorectal carcinoma (CRC) is the third most common cancer in the United States, with an estimated 150,000 new cases occurring annually. Early detection of clinically relevant colorectal neoplasia (CRN), i.e., CRC and advanced colorectal adenomas (A-CRA), is the best way to improve survival. However, available screening modalities are impractical due to invasiveness and cost (i.e., colonoscopy) or insufficient diagnostic accuracy (i.e., fecal-based blood tests). A better approach to screening and surveillance would be highly desirable. Abnormal DNA methylation is an important epigenetic mechanism that has been strongly implicated in the pathogenesis and progression of colorectal neoplasia. Aberrant DNA methylation is detectable in serum making it an ideal candidate biomarker species for non-invasive screening. Previous studies have achieved limited success in developing definitive sets of methylation biomarkers for CRC screening due non-comprehensive approaches, and a failure to include all CRNs as meaningful targets for clinical discovery. Also, cohorts used in serum-based studies have been insufficiently powered and lacked independent validation sets. In this proposal, innovative strategies will be applied to permit genome-scale methylation mapping using tissues and sera from patients with CRN, and compared with tissues and sera from individuals without CRN. A novel and powerful new approach is being proposed to identify new biomarkers and methylation targets with the highest sensitivity and specificity, and will be validated using large, well- characterized sample sets through the following Specific Aims.
Aim 1 : Candidate DNA methylation biomarkers will be discovered using next generation bisulfite sequencing in matched tissue and serum from patients with CRN and individuals with a normal colon.
Aim 2 : Candidate serum methylation biomarkers will be discovered that distinguish patients with CRN vs. those without CRN, and validated biomarkers using quantitative PCR assays.
Aim 3 : Clinical validation of prioritized serum methylation biomarkers identified in Aim 2b will be performed in asymptomatic average risk individuals. The innovation of this project is based upon the first use of a novel, next generation sequencing-based approach for identifying methylation-based biomarkers using a genome-scale assay for methylation sites linked to colorectal neoplasia, and validating these newly discovered biomarkers using a large, well-characterized cohort of patients with CRN and controls. The long-term goal and potential impact of this project is to develop a sensitive, specific, non-invasive and inexpensive diagnostic test for early colorectal neoplasia.

Public Health Relevance

We will perform a comprehensive and genome-scale evaluation of methylation biomarkers in plasma samples as potential noninvasive biomarkers for the early detection and prevention of colorectal cancers and precancerous lesions. Successful identification of methylation biomarkers will exert a substantial diagnostic and prognostic impact on the management of this fatal disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA181572-03
Application #
9088377
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vydelingum, Nadarajen A
Project Start
2014-05-21
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Wang, Wei; Kandimalla, Raju; Huang, Hao et al. (2018) Molecular subtyping of colorectal cancer: Recent progress, new challenges and emerging opportunities. Semin Cancer Biol :
Ravindranathan, Preethi; Pasham, Divya; Balaji, Uthra et al. (2018) A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer. Sci Rep 8:13869
Ozawa, Tsuyoshi; Kandimalla, Raju; Gao, Feng et al. (2018) A MicroRNA Signature Associated With Metastasis of T1 Colorectal Cancers to Lymph Nodes. Gastroenterology 154:844-848.e7
Kandimalla, Raju; Gao, Feng; Matsuyama, Takatoshi et al. (2018) Genome-wide Discovery and Identification of a Novel miRNA Signature for Recurrence Prediction in Stage II and III Colorectal Cancer. Clin Cancer Res 24:3867-3877
Ruiz-Bañobre, Juan; Goel, Ajay (2018) DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers. Gastroenterology :
Perea, José; García, Juan L; Corchete, Luis et al. (2018) Redefining synchronous colorectal cancers based on tumor clonality. Int J Cancer :
Toden, Shusuke; Ravindranathan, Preethi; Gu, Jinghua et al. (2018) Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer. Sci Rep 8:3335
Weng, Wenhao; Liu, Na; Toiyama, Yuji et al. (2018) Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer 17:16
Takehara, Yuko; Nagasaka, Takeshi; Nyuya, Akihiro et al. (2018) Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors. J Transl Med 16:5
Busch, Evan L; Galanko, Joseph A; Sandler, Robert S et al. (2018) Lifestyle Factors, Colorectal Tumor Methylation, and Survival Among African Americans and European Americans. Sci Rep 8:9470

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