Associations between Smoking, Alcohol Consumption, and Colorectal Cancer, Overall and by Tumor Microsatellite Instability Status

Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 09/2009; 18(10):2745-50. DOI: 10.1158/1055-9965.EPI-09-0517
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Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors.
We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor.
Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal cancer [odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; P(trend) = 0.03], and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for >30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR, 1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR, 1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02).
We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC.

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Available from: Joanne Patricia Young, Jan 31, 2014
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    • "The hypermethylation of the MLH1 promoter is also the predominant cause of MSI high (MSI-H) in sporadic tumors [15]. MSI-H cancers with methylated MLH1 are distinct from the rest of CRC by delayed onset and association with the female gender [16]. On the other hand, CRC cases without altered MMR genes show low-frequency MSI (MSI-L) or are microsatellite stable (MSS) [14]. "
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    ABSTRACT: Mismatch repair (MMR) genes are known to be frequently altered in colorectal cancer (CRC). Both genetics and epigenetics modifications seems to be relevant in this phenomenon, however it is still not clear how these two aspects are interconnected. The present study aimed at characterizing of epigenetic and gene expression profiles of MMR genes in sporadic CRC patients from the Czech Republic, a country with one of the highest incidences of this cancer all over Europe. Expression levels and CpG promoter methylation status of all MMR genes were evaluated in DNA from tumor and adjacent mucosal samples of 53 incident CRC patients. We have found significantly increased transcription levels in EXO1 gene in tumor tissues (P = 0.05) and significant over-expression of MSH3 gene in colon tumors when compared to adjacent mucosal tissues (P = 0.02). Interestingly, almost all MMR genes were differently expressed when localization of tumors was compared. In particular, colon tumors showed an up-regulation of EXO1, MSH2, MSH3, MSH6, and PMS2 genes in comparison to rectal tumors (P = 0.02). Expression levels of all MMR genes positively correlated between each other. The promoter methylation of MLH1 gene was observed in 9% of CRC tissues only. In our study, we have observed different pattern of MMR genes expression according to tumor localization. However, a lack of association between methylation in MMR genes and their corresponding expressions was noticed in this study, the relationship between these two aspects is worthy to be analyzed in larger population studies and in pre-malignant stages.
    BMC Medical Genetics 01/2014; 15(1):17. DOI:10.1186/1471-2350-15-17 · 2.08 Impact Factor
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    • "recent evidence suggests that smoking is differentially associated with certain tumour molecular phenotypes of colorectal cancer (CRC), such as tumours that display microsatellite instability (MSI), BRAF V600E mutation, or the CpG island methylator phenotype (CIMP) (Samowitz et al, 2006; Curtin et al, 2009; Poynter et al, 2009; Limsui et al, 2010; Ogino et al, 2011; Nishihara et al, 2013). The influence of smoking on CRC survival is inconclusive (Curtin et al, 2009; Limsui et al, 2010; Ogino et al, 2011). "
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    ABSTRACT: Background: Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis. Methods: A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and other relevant data were collected by questionnaire after cancer diagnosis, using a referent period of ‘2 years before diagnosis' to capture pre-diagnosis information. Molecular analyses of microsatellite instability (MSI) status and BRAF V600E mutation status were performed in tumour tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major prognostic factors. Results: Compared with never smokers, all-cause mortality (overall survival, OS) was higher for current (HR: 1.78; 95% CI: 1.04–3.06), but not for former (HR: 1.06; 95% CI: 0.71–1.59) smokers. The associations of cigarette smoking with the study outcomes were higher among patients with ⩾40 pack-years of smoking (OS: HR: 1.72; 95% CI: 1.03–2.85; disease-free survival (DFS: HR: 1.99; 95% CI: 1.25–3.19), those who smoked ⩾30 cigarettes per day (DFS: HR: 1.80; 95% CI: 1.22–2.67), and those with microsatellite stable (MSS) or MSI-low tumours (OS: HR: 1.38; 95% CI: 1.04–1.82 and DFS: HR: 1.32; 95% CI: 1.01–1.72). Potential heterogeneity was noted for sex (DFS HR: 1.68 for men and 1.01 for women: P for heterogeneity=0.04), and age at diagnosis (OS: HR: 1.11 for patients aged <60 and 1.69 for patients aged ⩾60: P for heterogeneity=0.03). Conclusions: Pre-diagnosis cigarette smoking is associated with worsened prognosis among patients with CRC.
    British Journal of Cancer 01/2014; 110(5). DOI:10.1038/bjc.2014.6 · 4.84 Impact Factor
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    • "Chronic consumption of non-steroidal anti-inflammatory drugs, hormone replacement therapy and statins are protective [7], [8]. The role of other lifestyle factors such as tobacco smoking [9], [10] or alcohol consumption [11], [12], [13], [14], [15], [16] remains inconclusive. Alcohol consumption has been reported to be associated with modest increased risks of CRC in some studies [17], but cancer risk may differ by tumor molecular subtype and anatomical site. "
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    ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.
    PLoS ONE 11/2013; 8(11):e80158. DOI:10.1371/journal.pone.0080158 · 3.23 Impact Factor
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