Neag Comprehensive Cancer Center

Farmington, CT, United States

Neag Comprehensive Cancer Center

Farmington, CT, United States
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Drew D.A.,Max Delbrück Center for Molecular Medicine | Drew D.A.,Neag Comprehensive Cancer Center | Goh G.,Clinical Translational Science Institute | Goh G.,University of Connecticut | And 13 more authors.
Cancer Causes and Control | Year: 2016

Purpose: Based on suggestive findings from a recent study of high-risk Japanese patients, we sought to determine whether the risk of colorectal polyps associated with smoking may be modified by daily use of aspirin in an analysis of a large US screening population. Methods: This is a cross-sectional study of 2,918 consecutive colonoscopy patients at a university hospital over a 30-month period. Data were abstracted from electronic medical records. Multivariate models of polyp counts were used to examine the competing risks of smoking and aspirin use. Models were further stratified by polyp location (proximal vs. distal) and pathologic subtype (dysplastic vs. serrated). Results: Incidental rate of polyps was higher among active smokers [incidence rate ratio (IRR) 1.72; 95 % confidence interval (CI) 1.46–2.02] and lower among daily aspirin users (IRR 0.73; 95 % CI 0.61–0.86) compared to those who used neither. Smoking interacts significantly with aspirin use resulting in loss of aspirin protection (IRR 1.69; 95 % CI 1.28–2.24). Stratified analyses demonstrate that aspirin specifically reduces the risk of traditional dysplastic adenomas (IRR 0.72; 95 % CI 0.61–0.86) not serrated/hyperplastic polyps (IRR 0.92; 95 % CI 0.72–1.17) and that the modification of aspirin protection by smoking is primarily observed within the distal colorectum (p < 0.03). Conclusions: We report for the first time, in a typical risk US clinical population, a lack of protective association of aspirin for polyps among active smokers. Future prospective studies are recommended to confirm this mitigating effect in order to improve the precision of the growing evidence base about the chemopreventive benefit of aspirin in colorectal cancer. © 2015, Springer International Publishing Switzerland.


Mo A.,Max Delbrück Center for Molecular Medicine | Mo A.,Neag Comprehensive Cancer Center | Jackson S.,Thermo Fisher Scientific | Varma K.,Thermo Fisher Scientific | And 5 more authors.
Molecular Cancer Research | Year: 2016

Although the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here, the development of an ultrasensitive laser capture microdissection (LCM)/RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci (ACF) is described. ACF are the earliest identifiable preneoplastic lesion found within the human colon and are detected using highdefinition endoscopy with contrast dye spray. The current analysis focused on the epithelium of ACF with somatic mutations to either KRAS, BRAF, or APC, and expression patterns compared with normal mucosa from each patient. By comparing gene expression patterns among groups, an increase in a number of proinflammatory NF-kB target genes was identified that was specific to ACF epithelium, including TIMP1, RELA, and RELB. Distinct transcriptional changes associated with each somatic mutation were observed and a subset of ACF display BRAFV600E-mediated senescence-associated transcriptome characterized by increased expression of CDKN2A. Finally, LCM-captured ACF-associated stroma was found to be transcriptionally distinct from normal-appearing stroma, with an upregulation of genes related to immune cell infiltration and fibroblast activation. Immunofluorescence confirmed increased CD3+ T cells within the stromal microenvironment of ACF and an abundance of activated fibroblasts. Collectively, these results provide new insight into the cellular interplay that occurs at the earliest stages of colonic neoplasia, highlighting the important role of NF-κB, activated stromal fibroblasts, and lymphocyte infiltration. Implications: Fibroblasts and immune cells in the stromal microenvironment play an important role during the earliest stages of colon carcinogenesis. © 2016 American Association for Cancer Research.


Mo A.,Max Delbrück Center for Molecular Medicine | Jackson S.,Thermo Fisher Scientific | Devers T.J.,UConn Health | Rosenberg D.W.,Max Delbrück Center for Molecular Medicine | Rosenberg D.W.,Neag Comprehensive Cancer Center
Journal of Cellular Biochemistry | Year: 2016

Our incomplete understanding of the critical changes that accompany the earliest stages of tumor initiation provides a substantial hurdle for the development of novel intervention strategies for cancer prevention. Premalignant lesions are inherently difficult to characterize given their diminutive size, creating technical obstacles for accurate genetic profiling. Here, we describe an approach combining laser-capture microdissection (LCM) with targeted RNA-sequencing to study the transcriptional state of epithelial and stromal cells during the earliest detectable stage of human colorectal neoplasia, the aberrant crypt foci (ACF). We provide a robust and reproducible workflow for RNA isolation, library preparation, and expression profiling of laser-captured cells from frozen OCT-embedded tissue specimens. It is anticipated that the methodological approach outlined in this report will provide a framework for a broad range of microgenomics analyses that can be routinely applied to many other premalignant tissues. J. Cell. Biochem. 117: 2677–2681, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.


PubMed | Neag Comprehensive Cancer Center, Clinical Translational Science Institute, Max Delbrück Center for Molecular Medicine and UConn Health
Type: Journal Article | Journal: Cancer causes & control : CCC | Year: 2016

Based on suggestive findings from a recent study of high-risk Japanese patients, we sought to determine whether the risk of colorectal polyps associated with smoking may be modified by daily use of aspirin in an analysis of a large US screening population.This is a cross-sectional study of 2,918 consecutive colonoscopy patients at a university hospital over a 30-month period. Data were abstracted from electronic medical records. Multivariate models of polyp counts were used to examine the competing risks of smoking and aspirin use. Models were further stratified by polyp location (proximal vs. distal) and pathologic subtype (dysplastic vs. serrated).Incidental rate of polyps was higher among active smokers [incidence rate ratio (IRR) 1.72; 95 % confidence interval (CI) 1.46-2.02] and lower among daily aspirin users (IRR 0.73; 95 % CI 0.61-0.86) compared to those who used neither. Smoking interacts significantly with aspirin use resulting in loss of aspirin protection (IRR 1.69; 95 % CI 1.28-2.24). Stratified analyses demonstrate that aspirin specifically reduces the risk of traditional dysplastic adenomas (IRR 0.72; 95 % CI 0.61-0.86) not serrated/hyperplastic polyps (IRR 0.92; 95 % CI 0.72-1.17) and that the modification of aspirin protection by smoking is primarily observed within the distal colorectum (p < 0.03).We report for the first time, in a typical risk US clinical population, a lack of protective association of aspirin for polyps among active smokers. Future prospective studies are recommended to confirm this mitigating effect in order to improve the precision of the growing evidence base about the chemopreventive benefit of aspirin in colorectal cancer.

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