Principal Investigator: Ajay Goel
Funding Organization: Charles A Sammons Cancer Center, Baylor University Medical Center
Project Start: June, 2013
Project End: May, 2015
Colorectal cancer (CRC) is a potentially preventable disease; however, it still ranks as the third most common cancer worldwide, and the second leading cause of cancer-related deaths in the United States, with an estimated 50,000 deaths annually. CRCs develop by progression through a pre-invasive colorectal adenoma (CRA) stage. However, ~90% of CRAs are low-risk and do not progress to invasive cancer, and only advanced CRAs confer the highest risk of progression to invasive carcinoma; and are generally considered as the most relevant targets of CRC screening strategies. Therefore, early detection of CRC or advanced CRAs is the best approach towards CRC prevention. However, currently available screening modalities to diagnose these lesions are invasive, expensive and suffer from poor patient compliance, and fail to identify patients that are at higher risk for developing CRC. In this regard, cancer biomarkers, which can facilitate earlier diagnosis of CRC, are desperately needed. Non-coding RNAs, including microRNAs (miRNAs) and Long Intergenic Non-Coding RNAs (lincRNAs) have emerged as key players in regulating gene expression in cancer development. Alterations in the expression patterns of miRNAs and lincRNAs occurs frequently and very early, manifests in a cancer-specific manner, and can be readily measured in tissues, blood, and other body fluids from cancer patients – making them ideal substrates for biomarker development. Nevertheless, although a large number of studies on miRNA biomarkers, and to some extent on lincRNAs have been published in the recent years, few of these biomarkers have yet shown the promise for clinical use. This biomarker discovery and development process has been hampered primarily due to lack of comprehensiveness and robustness of the “biomarker discovery process”. Unfortunately, in the recent years, use of microarray-based platforms have been the mainstay for biomarker discovery, which we now realize have several serious limitations, which includes; a) their inability to keep up with the growing list of non-coding RNA targets being discovered every day, and as result permitted analysis of only a limited number of miRNAs and lincRNAs, and b) high signal-to-noise ratios that are inherent to most microarray-based platforms, making subsequent validation of the discovered signatures extremely challenging in subsequent quantitative PCR-based assays. Given our prior experience in the cancer biomarker development field, and recognition of the underlying issues that have plagued the cancer biomarker discovery, the present pilot project is conceived to address some of these concerns. In this project, we propose to perform “biomarker discovery” using the Next Generation Sequencing (NGS)-based expression profiling of non-coding RNAs (miRNA and lincRNA) in normal colon, CRA and CRC tissues, followed by “biomarker validation” of the most promising biomarkers in a large, independent collection of colorectal specimens. To the best of our knowledge, ours will perhaps be the first effort to develop non-coding RNA-based biomarkers for colorectal neoplasia using NGS-based technologies, which will undoubtedly be most comprehensive and likely yield novel and highly specific transcriptomic biomarkers that were virtually impossible to be discovered using microarray-based tools. If successful in discovering and validating a panel of novel non-coding RNA biomarkers in colorectal tissues, these studies will provide us the requisite rationale for further exploration of these tissue-specific biomarkers in feces and blood of patients with colorectal neoplasia.