Colorectal tumors have different fates. Kim and colleagues demonstrated that early adenomas in humans could grow, remain static, or even spontaneously regress as determined by longitudinally monitoring via virtual colonography (N Engl J Med. 357(14):1403-12, 2007). We found that early adenomas in the mouse had the same fates (Acad Radiol. 16(12):1475-82, 2009). Moreover, a significant percentage of adenomas eventually progress to invasive adenocarcinomas that occasionally metastasize to regional lymph nodes (Cancer Res. 69(14):5768-75, 2009). The progression of tumors from a benign to malignant state can now be meticulously detailed because of recent advances in micro-imaging. We plan to monitor tumors as they progress, collecting biopsies for histopathological assessment and molecular analysis (Aim 1). Transcriptional changes associated with progression can then be elucidated with DNA microarrays. The profile of adenomas that progress to invasive adenocarcinomas will be compared to the profile of adenomas that do not progress (Aim 2). This type of experiment is not feasible in humans because the clinical outcome of any tumor is unknowable. Identifying predictive biomarkers in a mouse model is an important first step towards identifying genes of interest in humans. Our current understanding of the genetic events leading to human colorectal cancer (CRC) is not sufficiently detailed to allow us to provide sophisticated prognostic information to patients based on the molecular characteristics of their tumors. More detailed information would lead to personalized risk stratification and screening recommendations for patients based on genetic changes present within their tumors. This approach would minimize the risks garnered by unnecessary screening tests, while maximizing the chances that high-risk patients undergo more appropriately timed surveillance. It could also guide novel strategies for chemoprevention and treatment of CRC.

Public Health Relevance

Colorectal cancer is the second leading cause of cancer-related mortality in the United States. The current gold standard for screening is colonoscopy, which identifies potentially precancerous polyps or adenomas as well as cancerous lesions. Biomarkers that predict tumor progression would be invaluable to clinicians as they design personalized screening schedules and preventive strategies for each patient.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-D (M1))
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Umar, Asad
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University of Wisconsin Madison
Internal Medicine/Medicine
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United States
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Hadac, Jamie N; Miller, Devon D; Grimes, Ian C et al. (2016) Heterochromatin Protein 1 Binding Protein 3 Expression as a Candidate Marker of Intrinsic 5-Fluorouracil Resistance. Anticancer Res 36:845-52
Hadac, Jamie N; Leystra, Alyssa A; Paul Olson, Terrah J et al. (2015) Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence. Cancer Prev Res (Phila) 8:952-61
Paul Olson, Terrah J; Hadac, Jamie N; Sievers, Chelsie K et al. (2014) Dynamic tumor growth patterns in a novel murine model of colorectal cancer. Cancer Prev Res (Phila) 7:105-13