Program Official

Principal Investigator

William Mallory
Awardee Organization

Fred Hutchinson Cancer Center
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

(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.


  • Guo Y, Ayers JL, Carter KT, Wang T, Maden SK, Edmond D, Newcomb P P, Li C, Ulrich C, Yu M, Grady WM. Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15. Aging cell. 2019 Dec;18(6):e13013. Epub 2019 Aug 6. PMID: 31389184
  • Pickhardt PJ, Yee J, Johnson CD. CT colonography: over two decades from discovery to practice. Abdominal radiology (New York). 2018 Mar;43(3):517-522. PMID: 29516105
  • Pooler BD, Kim DH, Matkowskyj KA, Newton MA, Halberg RB, Grady WM, Hassan C, Pickhardt PJ. Growth rates and histopathological outcomes of small (6-9 mm) colorectal polyps based on CT colonography surveillance and endoscopic removal. Gut. 2023 Jul 28. Epub 2023 Jul 28. PMID: 37507217
  • Snow SM, Matkowskyj KA, Maresh M, Clipson L, Vo TN, Johnson KA, Deming DA, Newton MA, Grady WM, Pickhardt PJ, Halberg RB. Validation of genetic classifiers derived from mouse and human tumors to identify molecular subtypes of colorectal cancer. Human pathology. 2022 Jan;119:1-14. Epub 2021 Oct 14. PMID: 34655611
  • Cao W, Pomeroy MJ, Liang Z, Abbasi AF, Pickhardt PJ, Lu H. Vector textures derived from higher order derivative domains for classification of colorectal polyps. Visual computing for industry, biomedicine, and art. 2022 Jun 14;5(1):16. PMID: 35699865
  • Kordahi MC, Stanaway IB, Avril M, Chac D, Blanc MP, Ross B, Diener C, Jain S, McCleary P, Parker A, Friedman V, Huang J, Burke W, Gibbons SM, Willis AD, Darveau RP, Grady WM, Ko CW, DePaolo RW. Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer. Cell host & microbe. 2021 Oct 13;29(10):1589-1598.e6. Epub 2021 Sep 17. PMID: 34536346
  • Tan J, Gao Y, Liang Z, Cao W, Pomeroy MJ, Huo Y, Li L, Barish MA, Abbasi AF, Pickhardt PJ. 3D-GLCM CNN: A 3-Dimensional Gray-Level Co-Occurrence Matrix-Based CNN Model for Polyp Classification via CT Colonography. IEEE transactions on medical imaging. 2020 Jun;39(6):2013-2024. Epub 2019 Dec 30. PMID: 31899419
  • Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology. 2021 Feb;160(3):690-709. Epub 2020 Dec 3. PMID: 33279516
  • Pickhardt PJ, Graffy PM, Weigman B, Deiss-Yehiely N, Hassan C, Weiss JM. Diagnostic Performance of Multitarget Stool DNA and CT Colonography for Noninvasive Colorectal Cancer Screening. Radiology. 2020 Oct;297(1):120-129. Epub 2020 Aug 11. PMID: 32779997
  • Ulrich CM, Gigic B, Böhm J, Ose J, Viskochil R, Schneider M, Colditz GA, Figueiredo JC, Grady WM, Li CI, Shibata D, Siegel EM, Toriola AT, Ulrich A. The ColoCare Study: A Paradigm of Transdisciplinary Science in Colorectal Cancer Outcomes. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2019 Mar;28(3):591-601. Epub 2018 Dec 6. PMID: 30523039
  • Pickhardt PJ, Pooler BD, Matkowskyj KA, Kim DH, Grady WM, Halberg RB. Volumetric growth rates of sessile serrated adenomas/polyps observed in situ at longitudinal CT colonography. European radiology. 2019 Sep;29(9):5093-5100. Epub 2019 Feb 11. PMID: 30741343
  • Luebeck GE, Hazelton WD, Curtius K, Maden SK, Yu M, Carter KT, Burke W, Lampe PD, Li CI, Ulrich CM, Newcomb PA, Westerhoff M, Kaz AM, Luo Y, Inadomi JM, Grady WM. Implications of Epigenetic Drift in Colorectal Neoplasia. Cancer research. 2019 Feb 1;79(3):495-504. Epub 2018 Oct 5. PMID: 30291105
  • Himbert C, Figueiredo JC, Shibata D, Ose J, Lin T, Huang LC, Peoples AR, Scaife CL, Pickron B, Lambert L, Cohan JN, Bronner M, Felder S, Sanchez J, Dessureault S, Coppola D, Hoffman DM, Nasseri YF, Decker RW, Zaghiyan K, Murrell ZA, Hendifar A, Gong J, Firoozmand E, Gangi A, Moore BA, Cologne KG, El-Masry MS, Hinkle N, Monroe J, Mutch M, Bernadt C, Chatterjee D, Sinanan M, Cohen SA, Wallin U, Grady WM, Lampe PD, Reddi D, Krane M, Fichera A, Moonka R, Herpel E, Schirmacher P, Kloor M, von Knebel-Doeberitz M, Nattenmueller J, Kauczor HU, Swanson E, Jedrzkiewicz J, Schmit SL, Gigic B, Ulrich AB, Toriola AT, Siegel EM, Li CI, Ulrich CM, Hardikar S. Clinical Characteristics and Outcomes of Colorectal Cancer in the ColoCare Study: Differences by Age of Onset. Cancers. 2021 Jul 29;13. (15). PMID: 34359718
  • Wang T, Maden SK, Luebeck GE, Li CI, Newcomb PA, Ulrich CM, Joo JE, Buchanan DD, Milne RL, Southey MC, Carter KT, Willbanks AR, Luo Y, Yu M, Grady WM. Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk. Clinical epigenetics. 2020 Jan 3;12(1):5. PMID: 31900199
  • Chang S, Gao Y, Pomeroy MJ, Bai T, Zhang H, Lu S, Pickhardt PJ, Gupta A, Reiter MJ, Gould ES, Liang Z. Exploring Dual-Energy CT Spectral Information for Machine Learning-Driven Lesion Diagnosis in Pre-Log Domain. IEEE transactions on medical imaging. 2023 Jun;42(6):1835-1845. Epub 2023 Jun 1. PMID: 37022248
  • 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
  • Pickhardt PJ, Pooler BD, Kim DH, Hassan C, Matkowskyj KA, Halberg RB. The Natural History of Colorectal Polyps: Overview of Predictive Static and Dynamic Features. Gastroenterology clinics of North America. 2018 Sep;47(3):515-536. Epub 2018 Jun 29. PMID: 30115435
  • Gigic B, van Roekel E, Holowatyj AN, Brezina S, Geijsen AJMR, Ulvik A, Ose J, Koole JL, Damerell V, Kiblawi R, Gumpenberger T, Lin T, Kvalheim G, Koelsch T, Kok DE, van Duijnhoven FJ, Bours MJ, Baierl A, Li CI, Grady W, Vickers K, Habermann N, Schneider M, Kampman E, Ueland PM, Ulrich A, Weijenberg M, Gsur A, Ulrich C, FOCUS Consortium, Ulrich C, Gsur A. Cohort profile: Biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer recurrence and survival - the FOCUS Consortium. BMJ open. 2022 Dec 22;12(12):e062930. PMID: 36549742
  • Grady WM, Yu M. Molecular Evolution of Metaplasia to Adenocarcinoma in the Esophagus. Digestive diseases and sciences. 2018 Aug;63(8):2059-2069. PMID: 29766388
  • Yu M, Moinova HR, Willbanks A, Cannon VK, Wang T, Carter K, Kaz A, Reddi D, Inadomi J, Luebeck G, Iyer PG, Canto MI, Wang JS, Shaheen NJ, Thota PN, Willis JE, LaFramboise T, Chak A, Markowitz SD, Grady WM. Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia. Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Sep 1;28(17):3761-3769. PMID: 35705525
  • Cao W, Pomeroy MJ, Zhang S, Tan J, Liang Z, Gao Y, Abbasi AF, Pickhardt PJ. An Adaptive Learning Model for Multiscale Texture Features in Polyp Classification via Computed Tomographic Colonography. Sensors (Basel, Switzerland). 2022 Jan 25;22. (3). PMID: 35161653
  • Yu M, Hazelton WD, Luebeck GE, Grady WM. Epigenetic Aging: More Than Just a Clock When It Comes to Cancer. Cancer research. 2020 Feb 1;80(3):367-374. Epub 2019 Nov 6. PMID: 31694907
  • Yu H, Wang X, Bai L, Tang G, Carter KT, Cui J, Huang P, Liang L, Ding Y, Cai M, Huang M, Liu H, Cao G, Gallinger S, Pai RK, Buchanan DD, Win AK, Newcomb PA, Wang J, Grady WM, Luo Y. DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer. Journal of the National Cancer Institute. 2023 Jan 10;115(1):52-61. PMID: 36171645
  • 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