We propose a multi-disciplinary approach combining molecular analyses with funded clinical studies to evaluate aberrant crypt foci (ACF) and other diminutive lesions (<5 mm) for their significance in cancer development in the distal and proximal colon. We propose that distal colon ACF are self-limiting lesions and that few if any of these mainly hyperplastic lesions progress to neoplasia. Although ACF possess oncogenic mutations (e.g. BRAF or KRAS), we hypothesize that these lesions mobilize signaling pathways comparable to oncogene-induced senescence (OIS) pathways described in other cell and tissue types. We will approach this problem by using confocal imaging techniques and sensitive nanofluidic proteomics to examine the relationship between oncogene activation and OIS within ACF (Specific Aim 1). In contrast to the distal colon, we propose in Specific Aim 2 that ACF in the proximal colon (particularly those with activated BRAF) are at higher risk for progression. We will determine whether BRAF-activated proximal ACF show less efficient OIS, possibly through aberrant DNA methylation, and more frequent microsatellite instability, relative to distal colon lesions. In addition to assessing regional differences in colon cancer progression, we will also evaluate regional differences in chemoprevention using a mouse model of proximal colon cancer driven by KRAS activation (Specific Aim 3). We will focus initially on atorvastatin, a chemoprevention agent that has shown promise but has recently become a concern for potentially increasing proximal colon cancer risk. We will also determine the impact of statin usage on molecular markers expressed in human ACF (obtained from a completed trial). In addition, we will develop and evaluate a novel BRAF activated mouse model that may be particularly useful for proximal cancer chemoprevention studies. Finally, in Specific Aim 4, we will test the hypothesis that the frequency and/or molecular features of ACF will provide an index marker for future or synchronous colon cancer risk. Successful completion of these studies is anticipated to provide important insight into the cancer risk associated with the presence of ACF and other diminutive lesions in the proximal and distal colon. The Translational Significance of our studies is that the paradigm for screening on the right side of the colon may change from identifying large lesions for removal to the inclusion of ACF and other diminutive lesions as biomarkers for cancer risk, or even as potential cancer precursors. This information could potentially shape clinical practice, with additional attention to (or removal of) ACF and other small lesions in the proximal colon and depending on the molecular features identified, a recommendation of more frequent surveillance colonoscopies.

Public Health Relevance

The colonic mucosa is exposed to a wide range of carcinogenic insults and assessing the cumulative tissue damage resulting from such exposures could provide important information for assessing an individual's colon cancer risk. We propose a multi-disciplinary approach combining molecular analysis with funded clinical studies to evaluate pre-neoplastic lesions in human subjects and in mouse models. Our studies are intended to determine the risk associated with these pre-neoplastic lesions in the proximal and distal colon to determine how they should be viewed and treated clinically.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OTC-B (02))
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Umar, Asad
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University of Connecticut
Other Basic Sciences
Schools of Medicine
United States
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Drew, David A; Mo, Allen; Grady, James J et al. (2018) Proximal Aberrant Crypt Foci Associate with Synchronous Neoplasia and Are Primed for Neoplastic Progression. Mol Cancer Res 16:486-495
Hanley, M P; Hahn, M A; Li, A X et al. (2017) Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene 36:5035-5044
Drew, David A; Goh, Gyuhyeong; Mo, Allen et al. (2016) Colorectal polyp prevention by daily aspirin use is abrogated among active smokers. Cancer Causes Control 27:93-103
Mo, Allen; Jackson, Stephen; Varma, Kamini et al. (2016) Distinct Transcriptional Changes and Epithelial-Stromal Interactions Are Altered in Early-Stage Colon Cancer Development. Mol Cancer Res 14:795-804
Mo, Allen; Jackson, Stephen; Devers, Thomas J et al. (2016) Targeted Transcriptional Profiling of Microdissected Biopsy Specimens Representing Early Colonic Neoplasia. J Cell Biochem 117:2677-2681
Giardina, Charles; Nakanishi, Masako; Khan, Awaad et al. (2015) Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas. Cancer Prev Res (Phila) 8:387-99
Montrose, David C; Nakanishi, Masako; Murphy, Robert C et al. (2015) The role of PGE2 in intestinal inflammation and tumorigenesis. Prostaglandins Other Lipid Mediat 116-117:26-36
Hanley, Matthew P; Rosenberg, Daniel W (2015) One-Carbon Metabolism and Colorectal Cancer: Potential Mechanisms of Chemoprevention. Curr Pharmacol Rep 1:197-205
Drew, David A; Devers, Thomas J; O'Brien, Michael J et al. (2014) HD chromoendoscopy coupled with DNA mass spectrometry profiling identifies somatic mutations in microdissected human proximal aberrant crypt foci. Mol Cancer Res 12:823-9
Drew, David A; Devers, Thomas; Horelik, Nicole et al. (2013) Nanoproteomic analysis of extracellular receptor kinase-1/2 post-translational activation in microdissected human hyperplastic colon lesions. Proteomics 13:1428-36

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