Adenoma Size and High Calcium Intake Are Independent Predictors of Cyclin D1 Overexpression: An Analysis of 339 Polyps
Catherine E Hagen, Angeline S Andrew, Zhongze Li, Mary Ann Greene, Martha E Goodrich, Lynn F Butterly, John A Baron, Allen J Dietrich, Amitabh Srivastava. Dartmouth-Hitchcock Medical Center, Lebanon, NH; Brigham and Women's Hospital, Boston, MA
Background: Cyclin D1 and COX2 are overexpressed in a subset of colorectal cancer (CRC), while Vitamin D may have an inhibitory role; orthinine decarboxylase (ODC) may be overexpressed in premalignant states. The role of these markers in precursors of CRC has not been systematically evaluated. The aim of this study was to evaluate Cyclin D1, ODC, Vitamin D, and COX2 expression in colonic adenomas and their correlation with patient characteristics, adenoma size, location, and CpG methylation (CIMP).
Design: Tissue from patients in the New Hampshire Colonoscopy Registry (NHCR) was used for tissue microarray. Demographic data and endoscopic findings were retrieved from the NHCR database. Immunostaining was graded for extent (0=0-5%, 1=5-25%, 2=25-50%, 3=50-75%, 4=>75%) and intensity (0=negative, 1=weak-moderate, 2=strong). Cyclin D1 was evaluated for pattern (confluent/patchy). Multivariate analysis to determine odds ratio for “low” (intensity 0-1, extent 1) or “high” (intensity 2, extent 2-4, confluent) expression in relation to patient age, sex, polyp location, size, vitamin and calcium intake, and CIMP was performed. 339 tubular adenomas (M/F: 211/128; mean age: 57.4 years) were examined. Diminutive (<5mm), small (5-9mm) and large (≥10 mm) adenomas comprised 36% (n=122), 50% (n=171) and 12% (n= 42) of the study group, respectively. Diminutive polyps were the referent group for analysis. Polyps with missing covariates were excluded.
Results: High intensity Cyclin D1 staining was present in 188 (63%) polyps, high extent in 165 (55%) and a confluent pattern in 41 (13.6%). High Cyclin D1 extent was significantly increased in large (OR 4.05; p=0.002) and small (OR 2.41, p<0.001) polyps. Confluent staining was significantly higher in small polyps (OR 7.44, p<0.001) and approached significance in large polyps (OR 3.42, p=0.08). High calcium intake was significantly associated with confluent staining (OR 8.34, p<0.001) and high intensity expression (OR 2.62, p=0.02). High Cyclin D1 expression was not associated with any of the analyzed CIMP loci. High COX2 expression was significantly decreased in small (OR 0.3, p=0.004) and large (OR 0.16, p=0.004) polyps. High ODC and Vitamin D expression did not correlate with any of the analyzed variables.
Conclusions: Overexpression of Cyclin D1 increases with adenoma size and high calcium intake, suggesting a role in the adenoma-cancer pathway. COX2 is significantly decreased in large adenomas, suggesting overexpression may not occur until a later stage in carcinogenesis.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 135, Tuesday Afternoon