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Patricia Thompson,
Denise Roe,
Liane Fales,
Julie Buckmeier,
Fang Wang,
Stanley R Hamilton,
Achyut Bhattacharyya,
Sylvan B Green,
Chiu-Hsieh Hsu,
H-H Sherry Chow,
Dennis J Ahnen,
C Richard Boland,
Russell I Heigh,
David E Fay,
Elena Martinez,
Elizabeth Jacobs,
Erin L Ashbeck,
David S Alberts, Peter Lance
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ABSTRACT: Cyclooxygenase (COX) inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women aged 40-80 years were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 µg daily as selenized yeast), or double placebo. The trial was initiated in November, 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared to placebo, as determined by surveillance colonoscopy performed 3-5 years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December, 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n=1,621) was completed in November, 2008. A further 200 patients with 1+ advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n=1,824) was completed in January, 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; BMI 29.1 ±5.1; 47% taking low-dose aspirin while on trial; 20% with 3+ adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type 2 diabetes will also be reported (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00078897.).
Cancer Prevention Research 10/2012; · 4.91 Impact Factor
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ABSTRACT: COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1β in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1β, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1β. Further analysis indicated that the major COX-2 product, prostaglandin E(2), directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1β. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1β in the fibroblasts.
Experimental Cell Research 08/2012; 318(19):2520-30. · 3.58 Impact Factor
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ABSTRACT: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.
Biochemical and Biophysical Research Communications 08/2012; 425(3):607-12. · 2.48 Impact Factor
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ABSTRACT: COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts.
Experimental Cell Research 06/2012; 318(16):2116-27. · 3.58 Impact Factor
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Jun Wang,
Amit D Joshi,
Román Corral,
Kimberly D Siegmund,
Loïc Le Marchand,
Maria Elena Martinez,
Robert W Haile,
Dennis J Ahnen,
Robert S Sandler, Peter Lance,
Mariana C Stern
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ABSTRACT: Diets high in red meat are established risk factors for colorectal cancer (CRC). Carcinogenic compounds generated during meat cooking have been implicated as causal agents. We conducted a family-based case-control study to investigate the association between polymorphisms in carcinogen metabolism genes (CYP1A2 -154A>C, CYP1B1 Leu432Val, CYP2E1 -1054C>T, GSTP1 Ile105Val, PTGS2 5UTR -765, EPHX1 Tyr113His, NAT2 Ile114Thr, NAT2 Arg197Gln and NAT2 Gly286Glu) and CRC risk. We tested for gene-environment interactions using case-only analyses (N = 577) and compared statistically significant results to those obtained using case-unaffected sibling comparisons (N = 307 sibships). Our results suggested that CYP1A2 -154A>C might modify the association between intake of red meat cooked using high temperature methods and well done on the inside and CRC risk (case-only interaction OR = 1.53; 95% CI = 1.19-1.97; p = 0.0008) and the association between intake of red meat heavily browned on the outside and rectal cancer risk (case-only interaction OR = 0.65; 95% CI = 0.48-0.86; p = 0.003). We also found that GSTP1 Ile105Val might modify the association between intake of poultry cooked with high temperature methods and CRC risk (p = 0.0035), a finding that was stronger among rectal cancer cases. Our results support a role for heterocyclic amines that form in red meat as a potential explanation for the observed association between diets high in red meat and CRC. Our findings also suggest a possible role for diets high in poultry cooked at high temperatures in CRC risk.
International Journal of Cancer 05/2011; 130(8):1898-907. · 5.44 Impact Factor
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Journal of Carcinogenesis 01/2011; 10:11.
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ABSTRACT: Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.
Human Genetics 01/2011; 129(5):503-12. · 5.07 Impact Factor
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ABSTRACT: Fibroblast growth factor-23 (FGF-23) is a phosphaturic peptide and a key component of an endocrine feedback loop along with the hormonal vitamin D metabolite 1,25(OH)(2)D. Vitamin D has been shown to be inversely related to colorectal neoplasia; therefore, we hypothesized that the effect of FGF-23 on vitamin D metabolite concentrations could have implications for the risk of colorectal neoplasia.
The purpose of this study was to prospectively evaluate the association between circulating concentrations of FGF-23 and the risk of metachronous (recurrent) colorectal adenomas. FGF-23 levels were assessed in 100 male and female participants from the Ursodeoxycholic Acid Trial, 50 of whom had a metachronous colorectal adenoma and 50 who did not.
Compared to the lowest tertile of FGF-23, the adjusted odds ratios (95% CIs) for the second and third tertiles were 2.80 (0.94 to 8.31) and 3.41 (1.09 to 10.67), respectively (P-trend=.03). In a linear regression model, there was also a statistically significant inverse relationship between FGF-23 and 1,25(OH)(2)D (β-coefficient=-1.2; P=.001). In contrast, no statistically significant trend was observed between FGF-23 and 25(OH)D concentrations (β-coefficient=0.55; P=.10).
The current work presents novel preliminary evidence of a relationship between FGF-23 and the risk for colorectal neoplasia. FGF-23 activity may be mediated through biologic effects on individual serum and colonic 1,25(OH)(2)D levels, or it may be independent from the vitamin D pathway. Further studies in larger populations are necessary for confirmation and expansion of these hypothesis-generating results.
Journal of Carcinogenesis 01/2011; 10:3.
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ABSTRACT: In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial.
PLoS ONE 01/2011; 6(10):e25141. · 4.09 Impact Factor
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ABSTRACT: Fort Defiance Indian Hospital and Tuba City Regional Health Care Center are two rural hospitals with limited availability of optical colonoscopy (OC) and other methods of colorectal cancer screening. Our goals were to determine whether adequate examinations could be obtained with remote supervision after brief onsite instruction and to share lessons learned in our experience with a remote CT colonography (CTC) screening program.
After brief onsite instruction, including performing a CTC examination on a volunteer to train the CT technologists, both sites began performing CTC using standard bowel preparation, fecal tagging, automatic insufflation, and low-dose technique. Studies were transferred to the University of Arizona Hospital for image quality assessment of stool, residual fluid, distention, and interpretation, with reports returned via the teleradiology information system. Clinical follow-up was performed on those patients referred for polypectomy or biopsy.
Three hundred twenty-one subjects underwent CTC, including 280 individuals referred for screening examinations (87%). Ninety-two percent of subjects (295/321) had acceptable amounts of residual stool, 91% (293/321) had acceptable levels of fluid, and 92% (294/321) had acceptable distention. Fourteen percent (44/321) of CTC patients had polyps 6 mm or larger in size, with a positive predictive value of 41% for those who subsequently underwent colonoscopy-polypectomy (11/27).
CTC can be introduced to rural underserved communities, performed locally, and interpreted remotely with satisfactory performance, thereby increasing colorectal cancer screening capacity. Important aspects of implementation should include technologist training, referring physician education, careful attention to image transmission, and clearly defined methods of communication with patients and referring providers.
American Journal of Roentgenology 11/2010; 195(5):1110-7. · 2.78 Impact Factor
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Asgeir Brevik,
Amit D Joshi,
Román Corral,
N Charlotte Onland-Moret,
Kimberly D Siegmund,
Loïc Le Marchand,
John A Baron,
Maria Elena Martinez,
Robert W Haile,
Dennis J Ahnen,
Robert S Sandler, Peter Lance,
Mariana C Stern
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ABSTRACT: A diet high in red meat is an established colorectal cancer (CRC) risk factor. Carcinogens generated during meat cooking have been implicated as causal agents and can induce oxidative DNA damage, which elicits repair by the base excision repair (BER) pathway.
Using a family-based study, we investigated the role of polymorphisms in 4 BER genes (APEX1 Gln51His, Asp148Glu; OGG1 Ser236Cys; PARP Val742Ala; and XRCC1 Arg194Trp, Arg280His, Arg399Gln) as potential CRC risk factors and modifiers of the association between diets high in red meat or poultry and CRC risk. We tested for gene-environment interactions using case-only analyses (n = 577) and compared statistically significant results with those obtained using case-unaffected sibling comparisons (n = 307 sibships).
Carriers of the APEX1 codon 51 Gln/His genotype had a reduced CRC risk compared with carriers of the Gln/Gln genotype (odds ratio (OR) = 0.15, 95% CI = 0.03-0.69, P = 0.015). The association between higher red meat intake (>3 servings per week) and CRC was modified by the PARP Val762Ala single-nucleotide polymorphisms (SNP; case-only interaction P = 0.026). This SNP also modified the association between higher intake of high-temperature cooked red meat (case-only interaction P = 0.0009).
We report evidence that the BER pathway PARP gene modifies the association of diets high in red meat cooked at high temperatures with risk of CRC.
Our findings suggest a contribution to colorectal carcinogenesis of free radical damage as one of the possible harmful effects of a diet high in red meat.
Cancer Epidemiology Biomarkers & Prevention 10/2010; 19(12):3167-73. · 4.12 Impact Factor
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Journal of the American College of Radiology: JACR 01/2010; 7(2):159-60.
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ABSTRACT: Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk.
We conducted a secondary analysis of the efficacy of UDCA to prevent colorectal adenoma in men (n = 804) and women (n = 388).
We found no reduction in risk of any metachronous adenoma with UDCA treatment in men or women. However, UDCA treatment significantly lowered the odds of advanced lesions [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.43-0.89] in men, but not women. We also observed significantly higher odds of advanced lesions with UDCA treatment in women who were younger (age, <65 years; OR, 3.24; 95% CI, 1.10-9.56), obese (body mass index, > or = 30 kg/m(2); OR, 5.45; 95% CI, 1.42-20.9), or in the highest tertile of total dietary fat (> or = 56.2 g/day; OR, 3.48; 95% CI, 1.35-8.95). In a multivariate model, the interactive effect of fat intake accounted for the modulating effects of age and body mass index in women.
Our findings support the use of UDCA for preventing advanced colorectal adenomas in men. The increased odds of adenoma among women with high fat intake suggest a previously unrecognized harm that warrants further study, especially given the chronic exposure to UDCA in patients with primary biliary cirrhosis and the increasing investigational use of UDCA for several other conditions.
Cancer Prevention Research 12/2009; 2(12):1023-30. · 4.91 Impact Factor
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ABSTRACT: Colorectal cancer can be prevented via screening by the detection and removal of colorectal adenomas. Few data exist on screening capacity by rural/urban areas. Therefore, the aims of this work were to evaluate current colorectal cancer endoscopy screening capacity and to estimate potential volume for rural and urban regions in Arizona. Gastroenterologists and colorectal surgeons practicing in Arizona completed a survey (n = 105) that assessed current colonoscopy and sigmoidoscopy screening and estimated future capacity. Resources needed to increase capacity were identified, and differences between rural and urban regions were examined. Responders were more likely to practice in an urban region (89.5%). Physicians reported performing 8,717 endoscopic procedures weekly (8,312 in urban and 405 in rural regions) and the vast majority were colonoscopies (91% in urban and 97% in rural regions). Urban physicians estimated being able to increase their capacity by 35.7% (95% confidence interval 34.7-35.7) whereas rural physicians estimated an increase of 53.1% (95% confidence interval 48.1-58.0). The most commonly cited resource needed to increase capacity was a greater number of physicians in urban regions (52.1%); while the top response in rural areas was appropriate compensation (54.6%). Lastly, 27.3% of rural physicians noted they did not need additional resources to increase their capacity. In conclusion, Arizona has the ability to expand colorectal cancer screening endoscopic capacity; this potential increase was more pronounced in rural as compared to urban regions.
Journal of Community Health 10/2009; 34(6):523-8. · 1.28 Impact Factor
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ABSTRACT: Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.
Modern Pathology 10/2009; 23(2):169-76. · 4.79 Impact Factor
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ABSTRACT: The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese.
We assessed the relation between metachronous neoplasia and the components of metabolic syndrome (MetS) as defined by the National Cholesterol Education Program's Adult Treatment Panel III in 2,392 participants of two previously conducted chemoprevention trials. Waist circumference, fasting plasma glucose, trigylcerides, high-density lipoprotein, and systolic and diastolic blood pressure were measured at baseline.
MetS classification was associated with increased odds of metachronous neoplasia among women [odds ratio (OR), 1.37; 95% confidence interval (95% CI), 1.01-1.85] but not among men (OR, 0.99; 95% CI, 0.81-1.21). High waist circumference in men (OR, 1.41; 95% CI, 1.15-1.72) and women (OR, 1.41; 95% CI, 1.05-1.90) and elevated fasting glucose in women (OR, 1.46; 95% CI, 1.09-1.96), as defined by Adult Treatment Panel III cutpoints, were associated with increased odds, whereas none of the other criteria were independently associated with metachronous neoplasia. When each trait was evaluated using quartiles, elevated glucose among women and large waist circumference among men were significantly associated with metachronous lesions. Exploratory analysis of waist circumference and fasting glucose suggested an interaction, where only the combination of large waist circumference and elevated glucose conferred significant increased odds of metachronous neoplasia among both men (OR, 1.36; 95% CI, 1.04-1.78; P(interaction) = 0.08) and women (OR, 1.83; 95% CI, 1.26-2.67; P(interaction) = 0.12).
These results suggest that, of the specific components of MetS, those that capture impaired glucose uptake increased the odds of metachronous neoplasia.
Cancer Epidemiology Biomarkers & Prevention 05/2009; 18(4):1134-43. · 4.12 Impact Factor
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ABSTRACT: Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer. APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild-type APC. Steady-state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild-type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear beta-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild-type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-kappaB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation revealed that AP-1 and NF-kappaB binding to the 5'-promoter of CXCL8 was induced by DCA. The beta-catenin transcription factor was bound to the 5'-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody-directed against CXCL8 or wild-type APC. CXCL8 exposure led to matrix metalloproteinase-2 production and increased invasion on laminin-coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors.
International Journal of Cancer 01/2009; 124(10):2270-80. · 5.44 Impact Factor
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Elizabeth T Jacobs,
Dennis J Ahnen,
Erin L Ashbeck,
John A Baron,
E Robert Greenberg, Peter Lance,
David A Lieberman,
Gail McKeown-Eyssen,
Arthur Schatzkin,
Patricia A Thompson,
María Elena Martínez
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ABSTRACT: A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.
American journal of epidemiology 01/2009; 169(6):657-66. · 5.59 Impact Factor
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ABSTRACT: Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3' untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5' UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene-environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3-2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1-2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts.
Carcinogenesis 12/2008; 30(3):472-9. · 5.70 Impact Factor
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Cancer Prevention Research 09/2008; 1(3):216. · 4.91 Impact Factor
