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Background 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. Methods 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 Results Recent BMI, modeled in 5 kg/[m.sup.2] 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/[m.sup.2], 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). Conclusion 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. DOI: 10.1093/jnci/djq011

Background Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models--Leiden, MMRpredict, [PREMM.sub.1,2], and [MMR.sub.pro]--to distinguish between those who did and did not carry DNA mismatch repair gene mutations. Methods We studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. all statistical tests were two-sided. Results Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to 0.96. Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P< .015) for MSH6-PMS2 and MSH2-MLH1 mutation carriers, respectively. For the Leiden, MMRpredict, and [PREMM.sub.1,2] models, correcting the risk scores for bias introduced by family size improved their power to discriminate between carriers and noncarriers. After correcting for family size, the best model was MMRpredict, which achieved a sensitivity of 94% (95% confidence interval [CI] = 73% to 99%) and a specificity of 91% (95% CI = 88% to 93%) and identified a smaller proportion of patients than the revised Bethesda criteria as those who should undergo additional molecular or immunohistochemical testing (11% vs 50%). Conclusion MMRpredict was the best-performing model for identifying colorectal cancer patients who are at high risk of carrying a DNA mismatch repair gene mutation and thus should be screened for Lynch syndrome.

Background Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer. Methods We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay. Tumor microsatellite instability (MSI) was determined with a polymerase chain reaction-based method; MSI status was assigned as high (MSI-H, [greater than or equal to]30% unstable markers among all markers tested), low (MSI-L, Results We observed strong associations between the MLH1 -93G>A polymorphism and MSI-H tumors among case patients from Ontario (P= .001) and Newfoundland (P= .003). When compared with the control populations, homozygosity for the MLH1 -93G>A variant allele was associated with MSI-H tumors among case patients in Ontario (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.65 to 6.30) and in Newfoundland (OR = 8.88, 95% CI = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% CI = 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% CI = 1.14 to 5.75). Genotype frequencies were similar among case patients with MSS and MSI-L tumors and control subjects, and the majority of homozygous variant carriers had MSS tumors. Among case patients from Ontario, an association between the MLH1 -93G>A polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed. Conclusion In two patient populations, the MLH1 -93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.

Background: Bioelectrical impedance analysis (BIA) is widely used in clinics and research to measure body composition. However, the results of BIA validation with reference methods are contradictory, and few data are available on the influence of adiposity on the measurement of body composition by BIA. Objective: The goal was to determine the effects of sex and adiposity on the difference in percentage body fat (%BF) predicted by BIA compared with dual-energy X-ray absorptiometry (DXA). Design: A total of 591 healthy subjects were recruited in Newfoundland and Labrador. %BF was predicted by using BIA and was compared with that measured by DXA. Methods agreement was assessed by Pearson's correlation and Bland and Altman analysis. Differences in %BF among groups based on sex and adiposity were analyzed by using one-factor analysis of variance with Bonferroni correction. Results: Correlations between BIA and DXA were 0.88 for the whole population, 0.78 for men, and 0.85 for women. The mean %BF determined by BIA (32.89 [+ or -] 8.00%) was significantly lower than that measured by DXA (34.72 [+ or -] 8.66%). The cutoffs were sex specific. BIA overestimated %BF by 3.03% and 4.40% when %BF was 25% in men and >33% in women, respectively. Conclusions: BIA is a good alternative for estimating %BF when subjects are within a normal body fat range. BIA tends to overestimate %BF in lean subjects and underestimate %BF in obese subjects. KEY WORDS Percentage body fat, multifrequency bioelectrical impedance analysis, dual-energy X-ray absorptiometry, Newfoundland population, body composition