Periconceptional intake of folic acid prevents some neural tube defects (NTDs). Other nutrients may also contribute to NTD etiologies; a likely candidate is choline. Similar to folic acid, choline is involved in one-carbon metabolism for methylation of homocysteine to methionine. The authors investigated whether maternal periconceptional dietary intakes of choline and its metabolite betaine influence NTD risk. Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 424 NTD cases and with mothers of 440 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. Dietary intakes of choline were associated with reduced NTD risks. Controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates did not substantially influence risk estimates for choline. NTD risk estimates were lowest for women whose diets were rich in choline, betaine, and methionine. That is, for women whose intake was above the 75th percentile compared with below the 25th percentile for all three nutrients, the odds ratio was 0.17 (95% confidence interval: 0.04, 0.76). Study findings for dietary components other than folic acid offer additional clues about the complex etiologies of NTDs.

This study suggests that smoking cigarettes statistically significantly contributes to MSI in colon tumors. We estimate that approximately 21% of MSI in colon tumors may be attributable to cigarette smoking.

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Some studies have reported that p53 mutations or certain types of p53 mutation are associated with poor prognosis in colon cancer, while other studies have failed to show such a relationship. None of these previous studies was populationbased. We therefore evaluated the prognostic significance of p53 mutations in a large, population-based study of 1,464 individuals with colon cancer from Utah and California. Mutations in exons 5-8 were detected by SSCP analysis, followed by sequencing of aberrant bands. p53 mutations were identified in colon cancers from 665 of 1,464 (45.4%) individuals. p53 mutations were significantly more common in distal tumors (p < 0.01), tumors of relatively high stage (p ‫؍‬ 0.04), tumors without MSI (p < 0.01) and tumors without Ki-ras mutations (p < 0.01). In a univariate analysis, tumors with p53 mutations were associated with a significantly worse 5-year survival than those with wild-type p53 (53.4% vs. 58.8%, p ‫؍‬ 0.04); significantly worse prognosis also was seen with missense mutations, transitions, transversions, mutations affecting the structure of the p53 molecule, mutations within the ␤-sandwich motif and mutations in proximal tumors. In multivariate analyses, however, the only significant predictors of poor prognosis were G245 hot spot mutations (HRR ‫؍‬ 2.16, 95% CI 1.06 -4.40) and p53 mutations in proximal tumors (HRR ‫؍‬ 1.34, 95% CI 1.07-1.63). We conclude that overall p53 mutational status is not an independent predictor of poor prognosis in colon cancer. However, specific classes of mutations, namely, the G245 hot spot mutation and mutations in proximal tumors, are related to significantly worse survival even after adjusting for age and stage. © 2002 Wiley-Liss, Inc.Key words: p53; colon cancer; prognosis; microsatellite instability; Ki-ras p53 is a very commonly mutated gene in colon cancer. Some previous studies have reported that the presence of p53 mutations in colon cancer indicates a relatively poor prognosis, 1-16 while other studies have failed to show such a relationship. 17-27 Some of these studies directly evaluated p53 mutational status, 1-9,17-22 while many others used p53 overexpression by immunoperoxidase staining as an indirect measure of p53 mutations. 10 -16,23-27 Important structural motifs in the core domain of p53, that portion of the molecule responsible for DNA binding and the site of most mutations, have been identified. These motifs include a ␤-sandwich scaffold, 2 large loops (L2 and L3) that contain a zinc binding domain and an LSH, with the actual DNA binding surface being formed by parts of the 2 loops and the LSH. 28 Most p53 mutations are missense in nature, and it is possible that missense mutations affecting different structural motifs could have different effects on p53 function and, therefore, different prognostic significance. It also is possible to classify mutations in other ways, e.g., those that directly contact DNA vs. those that affect the overall structure of the p53 molecule or missense mutations vs. inactivating mutations. ...

Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. Other than relatively rare mutations in mismatch repair genes, the causes of MSI are not generally known. The purpose of this study was to determine if dietary intake of nutrients previously reported as being associated with colon cancer relate specifically to the MSI disease pathway. Data from a population-based case-control study of adenocarcinoma of the colon were used to evaluate associations between dietary intake and MSI. Participants were between 30 and 79 years of age at time of diagnosis and included both men and women. Dietary intake data were obtained from a computerized diet history questionnaire. MSI was evaluated in several ways: by a panel of 10 tetranucleotide repeats, and by 2 mononucleotide repeats, BAT-26 and TGF␤RII. A total of 1,510 cases had valid study data and tumor DNA on which we were able to obtain MSI status. Cases with and without MSI were compared with dietary data reported by 2,410 population-based controls to determine dietary associations that may be different for these 2 subsets of cases. We compared dietary intake for cases with and without MSI to further determine associations that are specific to the MSI disease pathway. Key words: colon cancer; diet; microsatellite instability; alcohol; cigarette smokingDiet has been repeatedly implicated in the etiology of colon cancer. 1,2 Inconsistencies in observed associations across studies could stem from individual dietary components being associated with certain types of tumors and disease pathways, but not with colon cancer overall. Ability to examine diet in relationship to specific disease end points, as determined by specific mutations in tumors, should enhance our understanding of the disease process and the role of diet in that process.Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. 3,4 People with inherited mutations of mismatch repair genes develop MSI in colon tumors; causes of MSI in sporadic colon tumors are largely unknown. 5 In our previous evaluation of lifestyle factors associated with MSI we found that cigarette smoking is specifically associated with MSI tumors, whereas other factors such as physical activity, body size, and use of aspirin and non-steroidal anti-inflammatory drugs appear to be related equally to MSIϩ and MSIϪ tumors. 6 Although dietary factors, to our knowledge, have not been examined with MSI in tumors, it is reasonable to hypothesize that components of diet, especially those that may be influenced by cigarette smoking, could influence development of unstable tumors. Alcohol could lead to unstable tumors independently or in combination with cigarette smoking. 7 Dietary antioxidants may decrease risk of unstable tumors through their role in reducing oxygen free radicals generated by cigarette smoke. 8 Other dietary factors hypothesized to influence cell growth and apoptosis, such as calcium, vitamin D and glycemic index, could be hypothesized as being associated with MSI in tumors. 9 In this ...

Our observed associations support observations that potential problems in glucose control are associated with NTD risk even among nondiabetic women.