Church, Timothy R

Several bacterial taxa enriched in inflammatory bowel diseases and colorectal cancer (CRC) are found in the oral cavity. We conducted a pilot study nested within a six-week aspirin intervention in a randomized placebo-controlled trial to test their response to aspirin intervention. Fifty healthy subjects, 50–75 years old, were randomized to receive 325 mg aspirin (n = 30) or placebo (n = 20) orally once daily for six weeks. Oral tongue swabs were collected at baseline and week six. We estimated the association between aspirin use and the temporal changes in the relative abundance of pre-specified genus level taxa from pre- to post-treatment. The temporal change in relative abundance differed for eight genus level taxa between the aspirin and placebo groups. In the aspirin group, there were significant increases in the relative abundances of Neisseria, Streptococcus, Actinomyces, and Rothia and significant decreases in Prevotella, Veillonella, Fusobacterium, and Porphyromonas relative to placebo. The log ratio of Neisseria to Fusobacterium declined more in the aspirin group than placebo, signaling a potential marker associated with aspirin intervention. These preliminary findings should be validated using metagenomic sequencing and may guide future studies on the role of aspirin on taxa in various oral ecological niches.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8–26.9) and 6.9 (5.0–9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6–2.9] for screening colonoscopy and 2.5 [1.8–3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8–18.5] and 2.9 [2.1–3.9], respectively) than HSgFOBT (20.8 [15.8–28.1] and 3.9 [2.9–5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68–0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable—as observed in the National Colonoscopy Study—offering screening colonoscopy can increase screening effectiveness.

AbstractTumor‐infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T‐lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T‐cells in colorectal tumor and histologically normal tissues with CRC‐specific and all‐cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin‐embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55–69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow‐up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC‐specific and all‐cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38–0.89) for CRC‐specific mortality and 0.82 (0.63–1.05) for all‐cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19–1.17) and 0.50 (0.27–0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC‐specific and all‐cause mortality. Although the association between tumor CD3+ score and all‐cause mortality was not significant, both higher CD3+ T‐lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC‐specific and all‐cause mortality.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Abstract Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study. Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer–specific death associated with each composite score. Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38–0.75; Ptrend = 0.0004) and 0.66 (0.51–0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18–0.51; Ptrend &lt; 0.0001) and 0.41 (0.27–0.63; Ptrend &lt; 0.0001) for colorectal cancer–related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer–related death. Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients. Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622–31. ©2016 AACR.