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1.  Randomized Controlled Trial of Acitretin Versus Placebo in Patients at High Risk for Basal Cell or Squamous Cell Carcinoma of the Skin (North Central Cancer Treatment Group Study 969251) 
Cancer  2011;118(8):2128-2137.
Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors’ knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high risk for NMSC.
The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged ≥18 years who had a history of ≥2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development.
Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15–1.13; 54% vs 74%; P = .13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P = .047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo.
Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power.
PMCID: PMC3365547  PMID: 21882176
acitretin; chemoprevention; basal cell carcinoma; squamous cell carcinoma; clinical trials
2.  Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention 
Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).
At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.
Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92).
Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
PMCID: PMC3566344  PMID: 23261228
lung cancer; chemoprevention; phase II clinical trial; sulindac; NSAIDs
3.  Noncathartic CT Colonography: Image Quality Assessment and Performance and in a Screening Cohort 
Cathartic bowel preparation is a major barrier for colorectal cancer screening. We examined noncathartic CT colonography (CTC) quality and performance using four similar bowel-tagging regimens in an asymptomatic screening cohort.
This prospective study included 564 asymptomatic subjects who underwent noncathartic CTC without dietary modification but with 21 g of barium with or without iodinated oral contrast material (four regimens). The quality of tagging with oral agents was evaluated. A gastrointestinal radiologist evaluated examinations using primary 2D search supplemented by electronic cleansing (EC) and 3D problem solving. Results were compared with complete colonoscopy findings after bowel purgation and with retrospective unblinded evaluation in 556 of the 564 (99%) subjects.
Of the 556 subjects, 7% (37/556) and 3% (16/556) of patients had 52 and 20 adenomatous polyps ≥ 6 and ≥ 10 mm, respectively. The addition of iodine significantly improved the percentage of labeled stool (p ≤ 0.0002) and specificity (80% vs 89–93%, respectively; p = 0.046). The overall sensitivity of noncathartic CTC for adenomatous polyps ≥ 6 mm was 76% (28/37; 95% CI, 59–88%), which is similar to the sensitivity of the iodinated regimens with most patients (sensitivity: 231 patients, 74% [14/19; 95% CI, 49–91%]; 229 patients, 80% [12/15; 95% CI, 52–96%]). The negative predictive value was 98% (481/490), and the lone cancer was detected (0.2%, 1/556). EC was thought to improve conspicuity of 10 of 21 visible polyps ≥ 10 mm.
In this prospective study of asymptomatic subjects, the per-patient sensitivity of noncathartic CTC for detecting adenomas ≥ 6 mm was approximately 76%. Inclusion of oral iodine contrast material improves examination specificity and the percentage of labeled stool. EC may improve polyp conspicuity.
PMCID: PMC3919488  PMID: 24059367
bowel preparation; colon cancer screening; CT colonography; patient compliance
4.  Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women 
Gut  2011;61(9):1299-1305.
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.
To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women’s Health Study of older women.
Exposure data were collected from Iowa Women’s Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.
PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.
In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.
PMCID: PMC3584677  PMID: 22027477
5.  Postmenopausal Hormone Therapy and Colorectal Cancer Risk in Relation to Somatic KRAS Mutation Status among Older Women 
Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Since colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women (Iowa Women’s Health Study [IWHS]).
The IWHS enrolled 41,836 randomly selected women, ages 55–69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).
PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI = 0.66–1.06; p = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI = 0.58–1.16; p = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI = 0.43–0.96; p = 0.03).
To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status, but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum).
Findings from this prospective cohort study provide novel insights regarding the molecular biology of PMH therapy-related CRC risk reduction.
PMCID: PMC3584684  PMID: 22337533
Postmenopausal hormone therapy; colorectal cancer; cohort study; KRAS
6.  A population-based study of prevalence and adherence trends in average risk colorectal cancer screening, 1997-2008 
Increasing colorectal cancer screening (CRCS) is important for attaining the Healthy People 2020 goal of reducing CRC-related morbidity and mortality. Evaluating CRCS trends can help identify shifts in CRCS, as well as specific groups that might be targeted for CRCS.
We utilized medical records to describe population-based adherence to average-risk CRCS guidelines from 1997-2008 in Olmsted County, MN. CRCS trends were analyzed overall and by gender, age, and adherence to screening mammography (women only). We also performed an analysis to examine whether CRCS is being initiated at the recommended age of 50.
From 1997-2008, the size of the total eligible sample ranged from 20585 to 21468 people. CRCS increased from 22% to 65% for women and from 17% to 59% for men (p<0.001 for both) between 1997 and 2008. CRCS among women current with mammography screening increased from 26% to 74%, and this group was more likely to be adherent to CRCS than all other subgroups analyzed (p<0.001).The mean ages of screening initiation were stable throughout the study period, with a mean age of 55 years among both men and women in 2008.
While overall CRCS tripled during the study period, there is still room for improvement.
Working to decrease the age at first screening, exploration of gender differences in screening behavior, and targeting women adherent to mammography but not to CRCS appear warranted.
PMCID: PMC3339802  PMID: 22144500
8.  Prospective evaluation of trans-fatty acid intake and colorectal cancer risk in the Iowa Women’s Health Study 
Concerns regarding the safety of dietary trans-fatty acids (tFAs) have generated recent public interest, scientific discussion and legislative action. Although most widely recognized as a risk factor for cardiovascular disease, associations between tFA intake and incident cancer have also been proposed. With respect to colorectal cancer (CRC), existing observational data remain limited and inconclusive. Therefore, we conducted a prospective evaluation of tFA intake and CRC risk, overall and by anatomic subsite, among participants in the Iowa Women’s Health Study, a population-based cohort of older women (ages 55–69 years at enrollment). Exposure data were collected at baseline using a semi-quantitative food-frequency questionnaire. Incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. CRC risks were estimated using Cox proportional hazards regression models. In total, 35,216 women met our inclusion criteria and 1229 CRC cases (631 proximal, 571 distal, 27 site not specified) were observed through 18 years of follow-up. Adjusting for age and total energy consumption, tFA intake in the fourth versus first quartile was not significantly associated with overall CRC risk (relative risk [RR] = 1.12; 95% confidence interval [CI] = 0.96–1.32). Similarly, risk estimates based on proximal (RR = 1.09; 95% CI = 0.87–1.37) and distal (RR = 1.18; 95% CI = 0.93–1.49) CRC subsites did not differ from unity. Multivariable adjustment yielded slightly attenuated risk estimates, but the observed associations were not meaningfully altered. Given these findings, tFA intake does not appear to be a major CRC risk factor, at least among older women.
PMCID: PMC2575073  PMID: 18767047
Colorectal cancer; trans fatty acids; dietary fat; cohort study
9.  DNA Mismatch Repair Gene Alterations in a Population-Based Sample of Young-Onset Colorectal Cancer Patients 
Background & Aims
Direct germline analysis could be used to screen high-risk patients for DNA mismatch repair gene mutations associated with Lynch Syndrome. To further evaluate this potential strategy, we examined the prevalence of MLH1, MSH2 and MSH6 mutations in a population-based sample of young-onset (age < 50 years) CRC cases.
Young-onset CRC cases were randomly selected from three Colon Cancer Family Registry sites (Cancer Care Ontario, Mayo Clinic, University of Southern California). Extracted DNA from peripheral blood leukocytes was shipped to Myriad Genetic Laboratories (Salt Lake City, UT) for MLH1, MSH2 and MSH6 sequencing, and duplication/deletion analyses for MLH1 and MSH2. Results were reported as: deleterious/suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry testing (IHC) in secondary analyses.
In 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% CI, 2.8%–9.9%), 12 had likely neutral alterations (6.2%; 3.2%–10.5%), 14 had variants of uncertain significance (7.2%; 4.0%–11.8%), 2 had both a likely neutral alteration and a variant of uncertain significance (1.0%; 0.1%–3.7%) and 156 had no alteration detected (80.0%; 73.7%–85.4%). Sensitivity, specificity, positive and negative predictive values for detecting deleterious/suspected deleterious mutations by ACII were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185) and by IHC testing were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18) and 99.3% (136/137).
In this population-based sample of young-onset CRC cases, germline MLH1, MSH2 and/or MSH6 mutations were more prevalent than previously reported for CRC patients overall. Yet, since only about 1 in 20 young-onset CRC cases had confirmed deleterious/suspected deleterious mutations, further comparative effectiveness research is needed to determine the preferred Lynch Syndrome screening strategy for this high-risk group.
PMCID: PMC3058119  PMID: 21056691
Lynch Syndrome screening; mutation prevalence; direct germline analysis; Colon Cancer Family Registry
10.  A Prospective Evaluation of C-reactive Protein Levels and Colorectal Adenoma Development 
Inflammation is hypothesized to play a role in colorectal tumorigenesis. Circulating levels of C-reactive protein (CRP), a serologic marker of the inflammatory response, have been positively associated with colorectal cancer development in some studies; however, there are limited data on the relation of CRP with colorectal adenomas, established precursors of colorectal cancer.
A nested case-control investigation of CRP levels and incident colorectal adenoma was conducted in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a randomized trial of 154,942 individuals designed to test the efficacy of flexible sigmoidoscopy on colorectal cancer mortality when performed once, and then repeated 3-5 years later. Serum CRP levels were measured in baseline blood specimens from participants who were free of polyps in the left-sided colorectum at the baseline screening procedure, but who were found at the subsequent screen to have at least one colorectal adenoma(N=356), and in a set of polyp-free, frequency-matched controls(N=396).
In a multivariable logistic regression model that included established colorectal adenoma risk factors, a 1-unit increase in log CRP level was associated with a 15% reduction in risk of developing colorectal adenoma (OR=0.85, 95%CI, 0.75-0.98, Ptrend=0.01). This association did not differ according to body size, smoking behavior, gender, use of non-steroidal anti-inflammatory drugs, or adenoma location.
High circulating CRP levels may be protective against colorectal adenoma development.
Though at contrast with mechanistic data on inflammation and colorectal tumorigenesis, this finding is not inconsistent with prior results on CRP and colorectal adenoma and warrants further investigation.
PMCID: PMC3051036  PMID: 21212059
11.  Randomized Phase II Trial of Sulindac, Atorvastatin and Prebiotic Dietary Fiber for Colorectal Cancer Chemoprevention 
Sulindac, atorvastatin or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects age ≥ 40 years, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required ≥ 5 rectal ACF at baseline. Intervention assignments were: (A) atorvastatin 20 mg qd; (B) sulindac 150 mg bid; (C) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (D) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and post-intervention, respectively. The median (standard deviation) for %ΔACF was 5.6 (−69–143%), −18.6 (−83–160%), −3.6 (−88-83%) and −10.0 (−100–117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within arm (p=0.12–0.59) nor between arm (p=0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also appeared to have similar effects on mucosal proliferation and apoptosis (p > 0.05 for each comparison). Data from this multi-center, phase II trial do not provide convincing evidence of CRC risk reduction from six month interventions with atorvastatin, sulindac or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.
PMCID: PMC3046804  PMID: 21209397
Colorectal cancer; chemoprevention; clinical trial; phase II
12.  Mayo Genome Consortia: A Genotype-Phenotype Resource for Genome-Wide Association Studies With an Application to the Analysis of Circulating Bilirubin Levels 
Mayo Clinic Proceedings  2011;86(7):606-614.
OBJECTIVE: To create a cohort for cost-effective genetic research, the Mayo Genome Consortia (MayoGC) has been assembled with participants from research studies across Mayo Clinic with high-throughput genetic data and electronic medical record (EMR) data for phenotype extraction.
PARTICIPANTS AND METHODS: Eligible participants include those who gave general research consent in the contributing studies to share high-throughput genotyping data with other investigators. Herein, we describe the design of the MayoGC, including the current participating cohorts, expansion efforts, data processing, and study management and organization. A genome-wide association study to identify genetic variants associated with total bilirubin levels was conducted to test the genetic research capability of the MayoGC.
RESULTS: Genome-wide significant results were observed on 2q37 (top single nucleotide polymorphism, rs4148325; P=5.0 × 10–62) and 12p12 (top single nucleotide polymorphism, rs4363657; P=5.1 × 10–8) corresponding to a gene cluster of uridine 5′-diphospho-glucuronosyltransferases (the UGT1A cluster) and solute carrier organic anion transporter family, member 1B1 (SLCO1B1), respectively.
CONCLUSION: Genome-wide association studies have identified genetic variants associated with numerous phenotypes but have been historically limited by inadequate sample size due to costly genotyping and phenotyping. Large consortia with harmonized genotype data have been assembled to attain sufficient statistical power, but phenotyping remains a rate-limiting factor in gene discovery research efforts. The EMR consists of an abundance of phenotype data that can be extracted in a relatively quick and systematic manner. The MayoGC provides a model of a unique collaborative effort in the environment of a common EMR for the investigation of genetic determinants of diseases.
PMCID: PMC3127556  PMID: 21646302
13.  A high-throughput 3-parameter flow cytometry-based cell death assay 
Apoptosis plays a role in many disease states, and the evaluation of novel therapeutics that alter the apoptotic cascade is an area of intense investigation. However, many generally available methods to evaluate cell death are either time consuming, imprecise, or both. We report a novel system that permits simultaneous evaluation of three apoptotic markers (cell membrane integrity, mitochondrial membrane potential, and cell cycle progression) with minimal technical manipulation. This system is particularly well-suited for initial efficacy and toxicology profiling of new candidate apoptosis-inducing or apoptosis-inhibiting agents.
PMCID: PMC3178655  PMID: 17226860
Apoptosis; High-throughout screen; Drug discovery; Mitochondria; Cell death; Necrosis
14.  Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes 
Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.
We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women’s Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).
Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation–positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation–positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation–negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).
In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation–positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.
PMCID: PMC2915616  PMID: 20587792
15.  Serum cytokine analysis in a positive chemoprevention trial: Selenium, Interleukin-2 and an association with squamous preneoplastic disease 
This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine down-regulated IL-2 by 9% (p=0.04), while celecoxib down-regulated IL-7 by 11% (p=0.006) and up-regulated IL-13 by 17% (p=0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall (OR=1.47, p=0.03) and among those with mild dysplasia at t0 (OR=2.53 p=0.001). An increase in IL-2 tertile from baseline to t10 was also non-significantly associated with worsening dysplasia for all participants (OR=1.32 p=0.098), and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR=2.0 p=0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR=2.52 p=0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, while celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10 month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect on reducing levels of IL-2.
PMCID: PMC2900463  PMID: 20587703
chemoprevention; interleukin-2; preneoplasia; gastrointestinal tract; selenium
16.  A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk 
Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.
This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model.
In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements.
Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users.
This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population.
PMCID: PMC2950115  PMID: 20615890
Colorectal Cancer; TagSNP; Folate Supplementation; Multivitamins; Microsatellite Instability; Colon subsite; ADA; ADH1C; AHCY; AMD1; CBS; DHFR; GIF; CUBN; MAT2A; MTHFD1; MTR; MTRR; SHMT1; TCN2; TYMS
17.  Genes involved with folate uptake and distribution and their association with colorectal cancer risk 
Cancer causes & control : CCC  2009;21(4):597-608.
Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH, and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically-confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n=29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1- rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR=1.00; 95% CI=0.81–1.23) or clinic-based (OR=0.75; 95% CI=0.44–1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.
PMCID: PMC2904058  PMID: 20037791
Folate; folate receptor 1 (FOLR1); solute carrier family 19 (SLC19A1); reduced folate carrier (RFC); folylpolyglutamate synthase (FPGS); gamma-glutamyl hydrolase (GGH); family-based; population-based; clinic-based; polymorphisms; colorectal cancer; case-control
18.  Case–Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status 
Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%–20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.
The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (≥30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.
Recent BMI, modeled in 5 kg/m2 increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m2, was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).
The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.
PMCID: PMC2841037  PMID: 20208017
19.  Parent of Origin Effects on Age at Colorectal Cancer Diagnosis 
Genomic imprinting refers to a parent-of-origin specific effect on gene expression. At least 1% of genes in the human genome are modulated in this manner. We sought evidence for genomic imprinting in colorectal cancer by studying the ages at diagnosis in the offspring of 2,061 parent-child pairs in which both parent and child were affected by non syndromic colorectal cancer. Families were ascertained through the colon Cancer Family Registry [] from both population-based and clinic-based sources. We found that the affected offspring of affected fathers were on average younger than offspring of affected mothers (55.8 vs 53.7 years; p=0.0003), but when divided into sons and daughters, this difference was driven entirely by younger age at diagnosis in daughters of affected fathers compared to sons (52.3 years vs 55.1 years; p=0.0004). A younger age at diagnosis in affected daughters of affected fathers was also observable in various subsets including families that met Amsterdam II Criteria, families that did not meet Amsterdam Criteria, and in families with documented normal DNA mismatch repair in tumors. Imprinting effects are not expected to be affected by the sex of the offspring. Possible explanations for these unexpected findings include: 1) an imprinted gene on the pseudoautosomal regions of the X chromosome; 2) an imprinted autosomal gene that affects a sex-specific pathway; or 3) an X-linked gene unmasked because of colonic tissue-specific preferential inactivation of the maternal X chromosome.
PMCID: PMC2877160  PMID: 19904757
imprinting; gender; pseudoautosomal; X-linked
20.  Genetic Variability in the MTHFR gene and colorectal cancer risk using the Colorectal Cancer Family Registry 
The MTHFR C677T TT genotype is associated with a 15%–18% reduction in colorectal cancer (CRC) risk but it is not clear if other variants of the gene are associated with CRC risk.
We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and CRC risk using a large family-based case control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry (CCFR).We assessed 22 TagSNPs, selected based on pairwise r2>95%, using Haploview Tagger and genotyped on the Illumina GoldenGate or Sequenom platforms. The association between SNPs and colorectal cancer was assessed using log additive, co-dominant, and recessive models.
From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased CRC risk overall (OR=0.81, 95% CI=0.63–1.04 and OR=0.82, 95% CI=0.64–1.07, respectively). The 677 TT genotype was associated with a decreased risk of microsatellite stable/microsatellite low tumors (OR=0.69, 95% CI=0.49–0.97) and an increased risk of microsatellite high tumors (OR= 2.22, 95% CI=0.91–5.43) (interaction p-value = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (interaction p-value = 0.02). No other SNP was associated with risk overall or within subgroups.
The 677 TT and 1298 CC genotypes may each be associated with a decrease in CRC risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to CRC risk.
PMCID: PMC2805460  PMID: 20056627
MTHFR; Colorectal Cancer; TagSNP; Folate Supplementation; Multivitamins; Microsatellite Instability; Colon subsite
21.  Esomeprazole and 325 mg/d Aspirin Reduce Tissue Concentrations of Prostaglandin E2 in Patients with Barrett’s Esophagus 
Gastroenterology  2012;143(4):917-926.e1.
Background & Aims
Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett’s esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled phase II trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin E2 (PGE2) in patients with BE with no dysplasia or low-grade dysplasia.
Participants were recruited through the multi-center Cancer Prevention Network and randomly assigned to groups that were given esomeprazole (40 mg, twice daily) in combination with an aspirin placebo (once daily) (Arm A; n=42), with 81 mg aspirin (once daily) (Arm B; n=63), or with 325 mg aspirin (once daily) (Arm C; n=63) for 28 days. We collected esophageal biopsies before and after the intervention period, to determine the absolute change in mean concentrations of PGE2 (the primary endpoint).
Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentrations of PGE2 was reduced by 67.6±229.68 pg/mL in Arm A, was reduced by 123.9±284.0 pg/mL in Arm B (P=.10 vs Arm A), and was reduced by 174.9 ±263.62 pg/mL in Arm C (P=.02 vs Arm A).
In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE2 patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients.
PMCID: PMC3458136  PMID: 22796132
esophageal cancer; NSAIDs; inflammation; esophagus
22.  Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Prostate Cancer 
The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear.
We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case–cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5–12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided.
Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; Ptrend = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; Ptrend = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (Ptrend = .38). A stronger association between insulin level and prostate cancer risk was observed among leaner men and among men who were less physically active at work. Crude prostate cancer incidence was 154 prostate cancers per 100 000 person-years in the lowest quartile of fasting serum insulin vs 394 prostate cancers per 100 000 person-years in the highest quartile.
Elevated fasting levels of serum insulin (but not glucose) within the normal range appear to be associated with a higher risk of prostate cancer.
PMCID: PMC2744728  PMID: 19700655
23.  Insulin, Glucose, Insulin Resistance and Incident Colorectal Cancer in Male Smokers 
Background & Aims
Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured using the homeostasis model assessment-insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk and none have reported associations based on HOMA-IR.
We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n=29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin x fasting glucose/22.5. Hazard ratios and 95% confidence intervals (HR; 95% CIs) were estimated using age-adjusted and multivariable-adjusted Cox proportional hazards regression models.
Median (IQR) values for serum insulin, glucose and HOMA-IR were 4.1 (2.9–7.2) mIU/L, 101 (94–108) mg/dL, and 0.99 (0.69–1.98) for case subjects and 4.1 (2.7–6.1) mIU/L, 99 (93–107) mg/dL, and 1.02 (0.69–1.53) for non-case subjects, respectively. Based on comparison of the highest versus lowest quartiles for each biomarker, insulin (HR=1.84; 95% CI=1.03–3.30) and HOMA-IR (HR=1.85; 95% CI=1.06–3.24) were significantly associated with incident CRC, while glucose was marginally associated with incident CRC (HR=1.70; 95% CI=0.92–3.13), in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (p trend= 0.12, 0.04 and 0.12, respectively) and multivariable adjustment generally attenuated the observed risk estimates.
Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia and/or insulin resistance as CRC risk factors. To our knowledge, these data represent the first reported associations between HOMA-IR and incident CRC.
PMCID: PMC1766481  PMID: 17162243
24.  Cigarette Smoking and Colorectal Cancer Risk by KRAS Mutation Status Among Older Women 
Existing data support a modest association between cigarette smoking and incident colorectal cancer (CRC) overall. In this study, we evaluated associations between cigarette smoking and CRC risk stratified by KRAS mutation status, using data and tissue resources from the Iowa Women’s Health Study (IWHS).
The IWHS is a population-based cohort study of cancer incidence among 41,836 randomly selected Iowa women, ages 55–69 years of age at enrollment (1986). Exposure data, including cigarette smoking, were obtained by self-report at baseline. Incident CRCs (n = 1,233) were ascertained by annual linkage with the Iowa Cancer Registry. Archived tissue specimens from CRC cases recorded through 2002 were recently requested for molecular epidemiology investigations. Tumor KRAS mutation status was determined by direct sequencing of exon 2, with informative results in 507/555 (91%) available CRC cases (342 mutation negative and 165 mutation positive). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between cigarette smoking variables and KRAS-defined CRC subtypes.
Multiple smoking variables were associated with increased risk for KRAS mutation-negative tumors, including age at initiation (P = 0.02), average number of cigarettes per day (P = 0.01), cumulative pack-years (P = 0.05), and induction period (P = 0.04), with the highest point estimate observed for women who smoked ≥ 40 cigarettes per day on average (RR = 2.38; 95% CI = 1.25–4.51; compared with never smokers). Further consideration of CRC subsite suggested that cigarette smoking may be a stronger risk factor for KRAS mutation-negative tumors located in the proximal colon than in the distal colorectum. None of the smoking variables were significantly associated with KRAS mutation-positive CRCs (overall or stratified by anatomic subsite).
Data from this prospective study of older women demonstrate differential associations between cigarette smoking and CRC subtypes defined by KRAS mutation status, and are consistent with the hypothesis that smoking adversely affects the serrated pathway of colorectal carcinogenesis.
PMCID: PMC3588167  PMID: 22349355
25.  Alcohol Intake and Colorectal Cancer Risk by Molecularly-Defined Subtypes in a Prospective Study of Older Women 
Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly-defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability (MSI-H or MSI-L/MSS), CpG island methylator phenotype (CIMP-positive or CIMP-negative) and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55–69 years at baseline (1986) and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Among alcohol consumers, the median intake (range) was 3.4 (0.9–292.8) g/day. Compared to non-consumers, alcohol intake levels of ≤ 3.4 g/day (RR = 1.00; 95% CI = 0.86–1.15) and > 3.4 g/d (RR = 1.06; 95% CI = 0.91–1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of ≤ 30 g/d and > 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or BRAF-defined CRC subtypes (p > 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly-defined subtypes, among older women.
PMCID: PMC3584678  PMID: 21900595
Colorectal Cancer; Alcohol; Older Women; Cohort Study

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