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Smoking and Colorectal Cancer in Lynch Syndrome: Results from the Colon Cancer Family Registry and The University of Texas MD Anderson Cancer Center

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clinical Cancer Research (Impact Factor: 8.72). 02/2010; 16(4):1331-9. DOI: 10.1158/1078-0432.CCR-09-1877
Source: PubMed

ABSTRACT

Lynch syndrome family members with inherited germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), and cases typically have tumors that exhibit a high level of microsatellite instability (MSI). There is some evidence that smoking is a risk factor for CRCs with high MSI; however, the association of smoking with CRC among those with Lynch syndrome is unknown.
A multicentered retrospective cohort of 752 carriers of pathogenic MMR gene mutations was analyzed, using a weighted Cox regression analysis, adjusting for sex, ascertainment source, the specific mutated gene, year of birth, and familial clustering.
Compared with never smokers, current smokers had a significantly increased CRC risk [adjusted hazard ratio (HR), 1.62; 95% confidence interval (95% CI), 1.01-2.57] and former smokers who had quit smoking for 2 or more years were at decreased risk (HR, 0.53; 95% CI, 0.35-0.82). CRC risk did not vary according to age at starting. However, light smoking (<10 cigarettes per day) and shorter duration of smoking (<10 years) were associated with decreased CRC risk (HR, 0.51; 95% CI, 0.29-0.91 and HR, 0.52; 95% CI, 0.30-0.89, respectively). For former smokers, CRC risk decreased with years since quitting (P trend <0.01).
People with Lynch syndrome may be at increased risk of CRC if they smoke regularly. Although our data suggest that former smokers, short-term smokers, and light smokers are at decreased CRC risk, these findings need further confirmation, preferably using prospective designs.

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Available from: Mala Pande, Jan 22, 2015
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    • "To adjust for this non-random ascertainment, we used the weighted cohort approach.[18]Age-specific incidence rates of CRC for MMR gene mutation carriers[19]were used to calculate sampling fractions to weight the proportion of affected and unaffected carriers in five-year age stratum so the proportion of affected carriers in each age group equalled that expected for mutation carriers in the population. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between each of 23 hTERT SNPs and CRC risk for MMR gene mutation carriers. "
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    ABSTRACT: Lynch syndrome is an inherited cancer-predisposing disorder caused by germline mutations in the DNA mismatch repair (MMR) genes but there is a high degree of variability in cancer risk observed among carriers, suggesting the existence of modifying factors. Our aim was to investigate variants within the hTERT gene as a potential colorectal cancer (CRC) risk modifier for MMR gene mutation carriers. We identified 1098 MMR gene mutation carriers (420 MLH1, 481 MSH2, 126 MSH6, 53 PMS2 and 18 EPCAM) from 330 families recruited from either family cancer clinics or population cancer registries of the Australasian Colorectal Cancer Family Registry between 1997 and 2012. Using weighted Cox regression after adjusting for ascertainment bias, we estimated associations between 23 SNPs within the hTERT gene and CRC risk. During 46,836 person-years observation, 392 (36%) carriers were diagnosed with CRC at a mean age of 42.2 (standard deviation 11.4) years. There was no evidence of association between any of the hTERT SNPs and CRC risk, overall and stratified by sex and MMR gene mutated, after adjustment for multiple testing. Our findings suggest no evidence for clinical utility of the SNPs within the hTERT gene in Lynch syndrome.
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    • "Age-specific incidence rates of CRC for MMR gene mutation carriers were previously estimated as described in detail by Pande et al (2010). These age-specific incidence rates were used to calculate sampling fractions to weight the proportion of affected and unaffected carriers in each age stratum, so that the proportion of affected carriers in each age group equalled the population proportions (Supplementary Table S1). "
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