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Colorectal cancer and adenoma adjacent to cancer exhibit distinct microRNA (miRNA) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miRNA expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HP), tubular adenomas (TA), tubulovillous adenomas or high-grade dysplasia (TVHG), and serrated polyps [sessile serrated adenoma/polyps (SSA/P) and traditional serrated adenomas (TSA)] in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRNAs by histologic type and logistic regression to identify miRNA predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRNAs differing in at least one of five histopathologic groups (FDR ≤0.05). In a comparison of HPNM versus TVHG, the top most upregulated and downregulated miRNAs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (downregulated; FDR P < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM + TA; CI, 95.6%), whereas miR-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG + TSA) from low-risk polyps (HPNM + TA + SSA/P; CI, 96.0%). For TSAs, miR-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222, and -214 discriminated between non-serrated and serrated histology. Our data support the presence of colorectal cancer–associated miRNA alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. Cancer Prev Res; 9(12); 942–9. ©2016 AACR.

1554 Background: Colorectal cancer incidence and mortality are increasing among individuals < 50 years of age. Data are limited regarding the epidemiology of colorectal adenomas in this younger age group. This study investigated and compared risk factors associated with recurrence of adenomas in individuals under and over 50 years of age. Methods: Pooled analyses from the Wheat Bran Fiber and Ursodeoxycholic Acid phase III, randomized, controlled clinical trials included 1,623 participants, aged 40-80 years. Each completed baseline questionnaires related to family history and lifestyle habits, had one or more colorectal adenomas removed at baseline, and had a follow-up colonoscopy during the trial (mean follow up 36 months). Univariate and multivariate logistic regression modeling estimated the association between age and colorectal adenoma recurrence, and evaluate multiple risk factors, while controlling for confounding factors. Results: A statistically significant increased trend was found for colorectal adenoma recurrence with increasing age ( Ptrend= < 0.001). Multivariate logistic regression revealed that risk factors significantly associated with adenoma recurrence in the ≥50 age group (n = 1,523) included history of previous polyps, characteristics of adenomas removed at baseline (multiple adenomas and villous feature), current smoking, and an increased waist circumference. Although risk profile in the < 50 age group (n = 95) shared similarities with that in the ≥50 age group (e.g., current smoking), there were a few notable differences: history of previous polyps was a more prominent predictor for recurrence for the < 50 (OR< 50 = 4.76 and OR≥50 = 1.33, Pinteraction = 0.042), whereas baseline characteristics of adenomas were more important for the ≥50 (multiple adenomas: OR< 50 = 0.40 and OR≥50 = 2.28, Pinteraction = 0.043). Conclusions: Predisposition to colorectal adenoma is a more important risk factor for recurrence in the < 50 as compared to the ≥50. Future studies need to identify susceptibility factors contributing to the increasing incidence of colorectal cancer in this younger age group.

TPS3627 Background: After standard treatment for stage 0-III colorectal cancer (CRC), patients remain at increased risk for metachronous high-risk adenomas (HRAs) and 2ndprimary CRCs. Polyamines, in excess, are implicated in CRC carcinogenesis. In prior CRC chemoprevention clinical trials, low doses of polyamine-inhibitory agents eflornithine (E) and sulindac (S) demonstrated impressive efficacy. In the prior phase III clinical trial of colorectal adenoma (CRA) patients the combination E+S vs. placebo for 3-years resulted in > 92% reduction in risk of HRAs. Utility of these agents in colon cancer survivors, however, is unknown. Methods: Eligibility:Patients age > 18 with colon or rectosigmoid adenocarcinoma, stage 0, I, II, or III are eligible. Patients with major cardiovascular risk factors (MI, CVA) are excluded, as are patients with hearing loss > 30dB at 4K Hz and below. Daily low dose aspirin is allowed. Study Design: Patients are enrolled 9-15 months postoperatively for a 3-year duration in the rand...

Background Interval colorectal cancer (CRC) occasionally is detected in patients who have recently undergone colonoscopy. Systematic evaluation of CRC detected after colonoscopy could identify ways to improve the quality and the outcome of colonoscopy. Methods This study examined cancer diagnoses in the course of the dietary Polyp Prevention Trial, a randomized study of a dietary intervention on recurrence of adenomatous polyps. An algorithm was developed to classify each cancer into one of 4 etiologies: (1) incomplete removal (cancer at the site of previous adenoma), (2) failed biopsy detection (cancer in an area of suspected neoplasia with negative biopsy specimens), (3) missed cancer (large, advanced stage cancer found at a short interval after colonoscopy), or (4) new cancer (small, early stage cancer after a longer time interval). Results Of 2079 patients, 13 had cancer detected over 5810 person years of observation (PYO) (2.2 cases/1000 PYO); 7/13 or 53.8% of patients had either a potentially "avoidable" cancer or one detectable at an earlier time interval because of incomplete removal (4/13) or missed cancer (3/13). Conclusions Interval cancer occurs despite colonoscopy. Improved quality of colonoscopy may have reduced cancer prevalence or resulted in earlier cancer detection in over 50% of prevalent cancers in the dietary Polyp Prevention Trial.

632 Background: Several epidemiological studies have demonstrated an association between bile acids (BA) and colorectal cancer. Despite this evidence, there are limited studies that examine the determinants of bile acids in humans. We conducted a secondary, cross-sectional analysis on 735 adenoma formers from a phase III adenoma prevention trial of ursodeoxycholic acid (URSO) who provided a fecal sample at their baseline visit. Methods: Fecal measures of primary bile acids cholic acid (CA) and chenodoxycholic acid (CDCA), as well as secondary bile acids, deoxycholic acid (DCA), lithocholic (LCA) were the outcome variables of interest. Dietary, non-dietary, medication use, genetic variation in the CYP7A1 gene (as single nucleotide polymorphisms (SNPs) and haplotypes), and physical activity, and characteristics of baseline adenoma were evaluated as correlates of fecal BAs. We used maximum likelihood methods to incorporate left-censoring in the BAs that had concentrations below the detection limit (BDL). These log-normal parametric survival models were used to fit potential predictors of fecal BA levels, stratifying by sex. The Akaike information criterion (AIC) was used to choose the best predictive model from each BA outcome. Model accuracy was assessed using leave-one-out cross validation and a likelihood-based measure of R2 and the Brier score. Results: LDL and cholesterol were predictors for primary bile acid CDCA in men and women, as was the use of pain medication (use of medication lowered BA levels). Genetic variation in CYP7A1 (as haplotypes and individual SNP's) was a significant determinant of CA level in both men and women. BMI was an important predictor for both men and women for DCA and CA. Presentation with tubular-villous histology was associated with LCA levels whereas proximal adenoma was an important predictor for CA levels, in men and women. Conclusions: This secondary analysis of a uniquely large dataset validates previous studies that suggest lifestyle and genetic factors influence colonic exposure to carcinogenic BAs. These findings also importantly highlight gender-specific differences in BA determinants that may explain colorectal cancer incidence differences between men and women.

Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting.To compare stool DNA and fecal blood testing for detection of screen-relevant neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas1 cm).Blinded, multicenter, cross-sectional study.Communities surrounding 22 participating academic and regional health care systems in the United States.4482 average-risk adults.Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy.Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P0.001) and 24% by HemoccultSensa (P0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P0.001) and 17% by HemoccultSensa (P0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030).Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers.Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.