Date of Completion

8-22-2014

Embargo Period

8-17-2016

Keywords

Colorectal cancer, cancer prevention, aberrant crypt foci, proteomics, genetics, human clinical trial, laser capture microdissection

Major Advisor

Daniel W. Rosenberg

Associate Advisor

Blanka Rogina

Associate Advisor

Kevin Claffey

Associate Advisor

Charles Giardina

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Colorectal cancer (CRC) prevention using screening colonoscopy relies upon the identification and removal of precancerous polyps or adenomas. Recently, an increase in CRC cases has been observed in individuals who have undergone screening colonoscopy before their next prescribed screening or surveillance interval, underscoring inherent limitations of routine colonoscopy as a complete preventive measure. Increasing evidence suggests that these “interval cancers” are most likely the product of missed or overlooked precancerous lesions. Specifically, interval cancers have a predilection for the proximal colon and their molecular features are associated with serrated polyps, lesions that due to their endoscopic morphology are difficult to detect and completely resect. To determine risk factors for precancerous lesions, especially those hard to detect endoscopically, we have performed a retrospective analysis of a gastroenterologist’s endoscopy practice in central Connecticut. Using statistical models, we associate demographic and lifestyle factors with polyp occurrence, pathology and colonic location. Interestingly, we demonstrate a potent interaction between smoking history and daily aspirin use that predicts polyp incidence and multiplicity. This finding has important clinical implications, as aspirin is a putative chemoprevention agent for CRC, yet this protective effect may be limited to certain sub-populations of patients.

Aberrant crypt foci (ACF) are macroscopic epithelial abnormalities that occur within the human colon and may represent the earliest precancerous lesion detectable by high-definition chromoendoscopy. ACF exhibit pathologic and molecular abnormalities similar to those observed in advanced neoplasia. Therefore, they may serve as an important surrogate marker for CRC risk, but recently their reliability has been questioned and they have rarely been studied in the proximal colon. We describe a comprehensive clinical trial designed to characterize human ACF molecularly and pathologically, in context of colonic location. Novel techniques, combining microdissection with nanoproteomic and high-throughput mass spectrometry-based genotyping platforms, were established as effective methods to detect mutations and measure downstream signaling consequences within biopsy specimens. Proximal ACF are demonstrated to be frequently dysplastic, possess oncogenic mutations and associate with synchronous neoplasia and ACF multiplicity. As such, they may serve as a surrogate marker of the at-risk colonic mucosa and, importantly, may represent a subset of the missed lesions that contribute to interval cancers. With careful consideration of these studies, clinicians may identify individuals who may benefit from shorter surveillance intervals or advanced endoscopic approaches, such as high-definition chromoendoscopy.

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