Program Official
Principal Investigator
William Mallory
Grady
Awardee Organization
Fred Hutchinson Cancer Center
United States
Fiscal Year
2021
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date
NIH RePORTER
For more information, see NIH RePORTER Project 6R01CA220004-06
(PQ6) Radiogenomics of colorectal polyps to assess benign proliferative vs. premalignant states.
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.
- Pooler BD, Kim DH, Matkowskyj KA, Newton MA, Halberg RB, Grady WM, Hassan C, Pickhardt PJ. Natural History of Colorectal Polyps Undergoing Longitudinal in Vivo CT Colonography Surveillance. Radiology. 2024 Jan;310(1):e232078. PMID: 38289210
- Matas J, Kohrn B, Fredrickson J, Carter K, Yu M, Wang T, Gui X, Soussi T, Moreno V, Grady WM, Peinado MA, Risques RA. Colorectal Cancer Is Associated with the Presence of Cancer Driver Mutations in Normal Colon. Cancer research. 2022 Apr 15;82(8):1492-1502. PMID: 35425963
- Hattangady NG, Carter K, Maroni-Rana B, Wang T, Ayers JL, Yu M, Grady WM. Mapping the core senescence phenotype of primary human colon fibroblasts. Aging. 2024 Feb 21;16(4):3068-3087. Epub 2024 Feb 21. PMID: 38385965
- Yu M, Carter KT, Baker KK, Redman MW, Wang T, Vickers K, Li CI, Cohen SA, Krane M, Ose J, Gigic B, Figueiredo JC, Toriola AT, Siegel EM, Shibata D, Schneider M, Ulrich CM, Dzubinski LA, Schoen RE, Grady WM. Elevated EVL Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023 Sep 1;32(9):1146-1152. PMID: 37294695