Colorectal cancer (CRC) is consequence of molecular alterations transforming normal epithelial cells into their neoplastic counterparts. Virtually, all CRCs derive from adenomas or serrated polyps, which begin forming in adulthood, and lead to cancer in 6-7% of the U.S. population by 80 years of age. However, since 30-50% or more of the population is affected by colon polyps, it is apparent that the vast majority of these lesions do not progress to CRC, but rather are benign proliferative lesions and not truly premalignant lesions. The molecular mechanisms that dictate which polyps are ?benign proliferative disease? and which are ?premalignant states? are essentially unknown. We propose to use an exceptional and unique clinical resource to determine whether the underlying genetic alteration profile, gene expression status, and/or epigenetic state of an early polyp governs its fate, using in vivo growth rate as a surrogate measure of malignant potential. The exceptional and unique resource that will permit us to do these studies is a large series of human colorectal polyps whose volumetric growth patterns have been serially assessed over time by CT colonography (CTC) prior to resection. In addition, volumetric textural analysis of CTC polyp data, which can be used to distinguish non-neoplastic proliferative lesions (hyperplastic polyps) from adenomas, will be correlated with growth rates. We will correlate results from whole exome sequencing, gene expression studies, and high-density methylation arrays with the observed CTC-based volumetric growth patterns, textural analysis and polyp histology. This ?radiogenomic? analysis of our series of benign and premalignant polyps will then allow us to test an innovative hypothesis about the mechanism(s) that determines a polyp?s fate. We have previously shown that many mutations and epigenetic alterations arise very early in polyp formation (the ?Big Bang? hypothesis of tumorigenesis) rather than sequentially, and that the initial tumor profile governs whether the polyp is premalignant or benign. Thus, some polyps might be ?born to be bad?. In this proposal, we will test the novel hypothesis that the genetic, transcriptional, or epigenetic state established at polyp formation dictates if a polyp is a benign proliferative lesion or a premalignant state.
Our SPECIFIC AIMS are: 1. To fully assess CTC data from a large cohort of patients with colorectal polyps that were followed in vivo by serial CTC prior to colonoscopic resection to accurately establish polyp growth rates and texture; 2. To determine whether mutations or transcriptional changes that occur early in tumorigenesis dictate polyp fate; and 3. To determine whether the epigenotype of a polyp correlates with growth behavior and the potential to become a CRC.
Colorectal cancer (CRC) primarily is a consequence of molecular alterations that occur in colon epithelial cells. These alterations lead to the formation of colon polyps that can evolve into CRC. Although virtually all CRCs arise from adenomatous polyps or serrated polyps, it is estimated that only approximately 5% of polyps ultimately progress to cancer. We will determine whether the epigenetic, transcriptional and genetic states established during the ?birth? of a polyp governs whether the polyp will be a benign proliferative lesion, with no potential to become cancer, or a premalignant lesion that will evolve into cancer. Our ability to address this question is the result of access to a highly unique and near singular set of human polyps that have been serially observed over time using CT colonography. These polyps have been observed to remain stable, which reflects a benign proliferative state, or to grow, which reflects the potential to become a CRC. Using cutting edge experimental methods, we will assess the genome wide genetic alterations, transcriptional changes, and epigenetic alterations in the polyps and determine whether the patterns of alterations established during polyp formation determine the ultimate fate of the polyp, which is to grow and progress to a deadly cancer or merely remain stable. Our studies have the potential to identify factors that affect the progression of polyps to CRC and will provide insight into the idea that some polyps may be ?born to be bad? rather than ?being born good and becoming bad over time?. Our findings will improve our ability to precisely identify the risk of CRC in specific individuals and will enhance our ability to prevent CRC.
|Pickhardt, Perry J; Pooler, Bryan Dustin; Kim, David H et al. (2018) The Natural History of Colorectal Polyps: Overview of Predictive Static and Dynamic Features. Gastroenterol Clin North Am 47:515-536|
|Pickhardt, Perry J; Yee, Judy; Johnson, C Daniel (2018) CT colonography: over two decades from discovery to practice. Abdom Radiol (NY) 43:517-522|