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The MTHFR C677T Polymorphism and Colorectal Cancer: The Multiethnic Cohort Study

¹ Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii and ² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Loïc Le Marchand, Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96813. Phone: 808-586-2988; Fax: 808-586-2082. E-mail: loic{at}crch.hawaii.edu

	Abstract

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Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the metabolism of folate, a nutrient that has been inversely related to colorectal cancer risk. The common C677T variant in the MTHFR gene results in a reduced activity of this enzyme, thereby increasing the availability of folate for the production of thymidylate and purine for DNA synthesis and repair. We investigated the association of the 677TT genotype with colorectal cancer in a case-control study of 822 cases and 2,021 controls nested within the Multiethnic Cohort Study. The Multiethnic Cohort Study is a large prospective study of men and women of Japanese, White, African American, Latino, and Native Hawaiian origin, residing in Hawaii and Los Angeles. After adjusting for covariates, we found an inverse association between colorectal cancer risk and the TT genotype, with odds ratios (OR; and 95% confidence intervals) for the CC, CT, and TT genotypes of 1.00, 1.01 (0.84-1.21), and 0.77 (0.58-1.03), respectively. This association was similar in both sexes, stronger at high levels of folate intake, and limited to light and nondrinkers (P for interaction with ethanol = 0.02). An analysis by subsite (rectum versus colon) and stage (regional/distant versus in situ/localized) showed that the inverse association with the TT genotype was limited to colon tumors, especially those diagnosed at an advanced stage. The OR for the TT versus CC genotype for early- and late-stage colon cancer was 0.88 (0.58-1.33) and 0.52 (0.32-0.85), respectively (P for difference in OR = 0.04). The frequency of the T allele was relatively low in African Americans (0.13) and Native Hawaiians (0.22), consistent with their greater likelihood of presenting at a late stage when diagnosed with colorectal cancer. This study corroborates previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, especially at high levels of folate and low levels of ethanol intake. It also suggests that this effect may be specific to advanced colon cancer.

	Introduction

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Low intake and plasma levels of folate and use of alcohol have been associated with an increased risk of colorectal cancer (1-6). It has been proposed that this association may result from the disruption of nucleotide synthesis and/or intracellular methylation and that alcohol increases risk by acting as a folate antagonist (7). Deficiency in folic acid has been shown to lead to massive uracil incorporation into DNA and to double-strand chromosome breaks, a feature commonly seen in colorectal cancer (7, 8). Because folic acid is the primary methyl donor in cellular metabolism, folate deficiency also results in global hypomethylation of the genome, as well as simultaneous focal hypermethylation of CpG islands, which may both disrupt gene expression (9). Inherited sequence variants in folate metabolism–related genes may interact with low folate intake to modulate the effect of this nutrient.

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism, regulating the flow of folate between these two important pathways: production of thymidylate and purines for DNA synthesis and supply of methyl groups for the synthesis of methionine and DNA methylation (10). A common C677T substitution in the MTHFR gene, converting an alanine to a valine, results in a thermolabile enzyme with decreased activity. A second variant (A1298C) has also been shown to reduce MTHFR activity but to a lesser extent than C677T (11). The 677T variant has been associated with a lower risk of colorectal cancer, especially at high levels of folate intake (10, 12). Alcohol intake has been found to negate this effect (11). In contrast, most studies of colorectal adenomas have reported a direct association with the polymorphism at low levels of folate intake (12). Other B vitamins (e.g., vitamins B6 and B12) act as coenzymes in the same metabolic pathway and may also interact with the MTHFR polymorphism (10, 12).

We investigated the association of the MTHFR C677T polymorphism with colorectal cancer in a large case-control study nested in the Multiethnic Cohort Study. Our aims were to compare effects at various levels of folate and alcohol intakes in the Multiethnic Cohort population, which is notable for its wide range of dietary intake (13) and use the large sample size to examine effects by sex, anatomic subsite, and stage at diagnosis, which has not been done in previous studies.

	Materials and Methods

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The design and baseline characteristics of the Multiethnic Cohort have been described in detail elsewhere (13). In short, participants are Hawaii and Los Angeles residents who entered the cohort from 1993 to 1996 by completing a 26-page mail questionnaire about demographic factors, lifestyle (including diet and smoking), medical history, medication use, family history of common cancers, and, for women, reproductive history and hormone use. The cohort included 96,810 men and 118,441 women ages 45 to 75 years at cohort creation in 1993. Twenty-six percent were Japanese American, 23% White, 22% Latino, 16% African American, 7% Native Hawaiian, and 6% other ethnic/racial origin. Colorectal cancer cases were identified through the Rapid Reporting System of the Hawaii Tumor Registry and through quarterly linkage to the Los Angeles County Cancer Surveillance Program, two cancer registries that are members of the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. This was complemented by annual linkages to the State of California's cancer registry. Incident colorectal cancer cases occurring since January 1995 and controls were contacted for donation of a blood sample. The median interval between diagnosis and blood draw was 14 months (interquartile range, 10-19) among cases. A sample of cohort participants was randomly selected to serve as controls at the onset of the nested case-control study. The selection was stratified by sex and race/ethnicity. Samples were collected at the subject's home, processed within 8 hours, and stored at –80°C. As of June 1999, the participation rate among cases was 74% and varied from 70% in African Americans to 81% in Latinos. The corresponding rate for controls was 66% and varied from 60% in African Americans to 71% in Whites.

The food frequency questionnaire asked about the frequency and amount of consumption for >140 food items during the last year. Photographs of foods, showing three different portion sizes, were used to facilitate quantification of intakes. Nutrients were computed by applying a food composition table to the daily grams of each food item and summing across items. The food composition data were primarily based on the U.S. Department of Agriculture's nutrient database (Handbook 8) and were supplemented with data from other research and commercial publications. A calibration study that compared diet reported on the questionnaire with three 24-hour recalls suggested that folate intake was adequately measured with correlation coefficients ranging across ethnic groups between 0.5 and 0.8 for women and 0.4 and 0.7 for men (14). Cohort members were asked about their usage during the last year of multivitamins/minerals and seven single vitamins. Supplemental folic acid intake was assessed from multivitamin usage. A composite nutrient content was assumed for multivitamins (15).

DNA was extracted from blood lymphocytes using a standard method (QIAamp DNA Blood Mini kit, Qiagen, Valencia, CA). Genotyping for the MTHFR C677T variant was carried out by PCR/RFLP as previously described (16). A subset of 826 female controls were also genotyped for the same variant in another study using the fluorogenic 5'-nuclease assay (TaqMan assay; ref. 17), resulting in perfect genotype concordance for 97% of the subjects.

The statistical analysis used unconditional logistic regression to compute odds ratios (OR) and 95% confidence intervals (95% CI) for exposures of interest (18). Fifty-one controls and 28 cases were excluded because of missing covariates, leaving 822 cases and 2,021 controls for the analysis. Genotypes were modeled as two dummy variables representing the three levels or as a gene dosage effect variable assigned a value of 1, 2, or 3 according to the number of variant alleles (zero, one, and two variant alleles, respectively). The final models were only adjusted for sex, age at blood draw, and ethnicity because further adjustment for other colorectal cancer risk factors (pack-years of cigarette smoking, body mass index, hours in vigorous activity, and dietary fiber and alcohol intakes) did not materially change the risk estimates (see Table 2). The likelihood ratio test was used to determine interaction among certain variables with respect to colorectal cancer. The test compares a main effects, no interaction model with a fully parameterized model containing all possible interaction terms for the variables of interest. Polytomous logistic regression was used to simultaneously estimate risk among controls and subgroups of cases, such as those diagnosed at a regional/distant stage versus in situ/localized stage and rectal versus colon cancer (19). A Wald test was used to statistically compare risk estimates across the case subgroups. Departure of the genotype distributions from the Hardy Weinberg equilibrium was tested with the ² test.

	Results

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After adjustment for ethnicity/race, sex and age at blood draw, the odds ratios for the MTHFR 677 CT and TT genotypes, compared with the CC genotype, were 1.01 (95% CI, 0.84-1.21) and 0.77 (95% CI, 0.58-1.03), with P for gene dosage effect = 0.18. These ORs were not modified after further adjustment for pack-years, body mass, vigorous physical activity, and dietary fiber and ethanol [1.0, 0.99 (95% CI, 0.81-1.20) and 0.78 (95% CI, 0.57-1.06); P for gene dosage effect, 0.19]. Consequently, this additional adjustment was not carried out in the rest of the analysis. The risk estimates for the CT and TT genotypes were similar in men [1.07 (95% CI, 0.53-1.15) and 0.78 (95% CI, 0.53-1.15); P for gene dosage, 0.46] and women [0.92 (95% CI, 0.49-1.22) and 0.75 (95% CI, 0.49-1.16); P for gene dosage, 0.21]. In other stratified analyses, the association with the TT genotype was statistically significant in Japanese Americans [OR for TT versus CC: 0.59 (95% CI, 0.36-0.95)], suggested for Whites [0.62 (95% CI, 0.34-1.15)] and not observed in Latinos [0.96 (95% CI, 0.56-1.15)]. There were only five cases each with the TT genotype for African Americans and Native Hawaiians and the risk estimates were unreliable in these groups.

Table 2 shows the joint effect of dietary folate and the TT genotype on colorectal cancer risk. The risk associated with the TT genotype was lowest among subjects with a high intake of folate. The OR for subjects with the TT genotype and total folate intake >median was significantly decreased (OR, 0.48; 95% CI, 0.33-0.72), compared with subjects with the CC or CT genotype and an intake median. However, the test for interaction was not statistically significant. In contrast, in an analysis of the joint effect of ethanol and the TT genotype (Table 2), the inverse association with the TT genotype was only observed among subjects with ethanol intake median (0.01 g/d; P for interaction, 0.02). The OR for the TT genotype among light and nondrinkers was 0.53 (95% CI, 0.34-0.82), whereas no corresponding decrease in risk with the TT genotype was observed among heavier drinkers. This pattern seemed to be similar in men and women and stronger for colon than rectal cancer (data not shown).

To explore whether the type of categorization used for the dietary variables had any effect on the relationships noted above, we reran these interaction models successively using tertiles (Table 3) and quartiles (not shown) for the dietary variables. Although there was no gradient in risk for the TT genotype across tertiles of folate, the protective effect for the TT genotype was strongest in the group with the highest total intake for folate. We also explored the joint effects of the TT genotype with intakes of other B vitamins (Table 3). The protective effect of the TT genotype was limited to individuals in the highest two intake tertiles of riboflavin and vitamin B6. The effect of TT was also much stronger in nondrinkers than in the two intake groups of ethanol.

	Discussion

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Our results bring additional evidence for an inverse association between the MTHFR 677TT genotype and colorectal cancer. This association was first reported in two male Harvard cohorts (20, 21) and was reproduced in five of eight case-control studies to date (reviewed in ref. 11). Four of five past studies suggested interactions between folate and the TT genotype, with the inverse association being greatest among persons with the highest intake or plasma levels of folate (16, 20-23). Both studies that investigated the modifying effect of alcohol found a significant interaction between the TT genotype and alcohol, by which the inverse association with TT was only seen at low levels of ethanol intake (20, 21). Our results for the Multiethnic Cohort Study are remarkably consistent with those findings. Of note is that, in our population, the inverse association with alcohol intake was negated at a level of alcohol intake corresponding to one drink per week. This is in contrast to the two (predominantly White) male Harvard cohorts in which the effect was found to be absent over a level of approximately one drink per day (20, 21). Reasons for this discrepancy are not immediately apparent because similar methods of assessing alcohol intake were used. It is also unlikely to be due to a possible modifying effect of ALDH2*2 (24), an allele that is common in Japanese, because the exclusion of this group from our analysis did not substantially modify the results (P for interaction, 0.08).

Fewer studies compared results by anatomic subsite but similar main effect risk estimates were reported for the colon and rectum in the Physicians' Health Study (21). We are not aware of any past report by stage at diagnosis. Because our design was that of a case-control study, a certain percentage of cases died before we could contact them (24.9% for colon cancer cases; 23.5% for rectal cancer cases). As a result, the genotype frequencies could be misrepresented in our cases if the MTHFR C677T polymorphism were associated with survival after diagnosis. Few studies of this relationship have been published and the data have been inconsistent. In a study of 365 nonadjuvant-treated colorectal cancer patients, the TT genotype was associated with improved survival, but this association did not persist after adjustment for stage (25). Among 51 stage III colon cancer patients treated with 5-fluorouracil (5-FU), a common treatment for advanced colorectal cancer, presence of the 677T allele had little effect on survival (26). However, a study of 43 patients with metastatic colorectal cancer receiving 5-FU therapy showed that carriers of the 677T allele (n = 26) were more likely to respond to treatment than noncarriers (27). A similar finding was observed among 98 colorectal patients with nonresectable liver metastases treated with 5-FU (28). However, this better response to 5-FU for T-allele carriers did not translate into a survival advantage in this study (28). 5-FU sensitivity was also tested in 19 human cancer cell lines (head and neck, breast, and digestive tract) and found to be independent from the C677T polymorphism (29). However, human HCT116 colon cancer cells transfected with mutant 677T human MTHFR cDNA were recently found to have a decreased MTHFR activity, a changed intracellular folate distribution, an accelerated growth rate, an increased thymidylate synthase activity, and an increased sensitivity to 5-FU (30). Overall, however, the small sample sizes of the clinical studies and the high likelihood of publication bias preclude any robust conclusions (31).

Although we did not have information on the type of chemotherapy regimen received by cases in our study, we used the information collected by our Surveillance, Epidemiology, and End Results registries to evaluate the effect of the TT genotype on colorectal cancer risk among those who received chemotherapy as first course of treatment and those who did not. These analyses were run for all cases, limited to only advanced cases, and by colon and rectum subsite, using all controls in each model. A similar inverse association was observed independently of whether the patients received chemotherapy or not. For example, for patients with regional/distant colorectal cancer who received chemotherapy as part of their first course of treatment (n = 195), the OR for the CC, CT, and TT genotypes were 1.00, 0.95 (95% CI, 0.69-1.31) and 0.57 (95% CI, 0.33-0.99), respectively (P for gene dosage, 0.09). The corresponding ORs for those patients with regional/distant colorectal cancer who did not receive chemotherapy (n = 150) were 1.00, 0.65 (0.44-0.92), and 0.68 (0.39-1.20; P for gene dosage, 0.05). In addition, our overall risk estimates for the TT genotype were very similar to those found in studies where DNA was obtained before diagnosis (20, 21). Finally, the specificity of effect for advanced tumors was only observed for colon cancer and not rectal cancer and the proportion of patients missed due to deaths before contact was similar for both subsites (see above). Thus, we found no evidence that our stage-specific findings could be explained by survival bias.

Interestingly, the lower frequency of the T allele in African Americans and Native Hawaiians and the finding of a specificity of its protective effect against advanced colorectal cancer are consistent with the late-stage presentation and poorer survival observed for the disease in these ethnic groups (32-34). Similarly, the stronger effect for the TT genotype suggested for Japanese would be consistent with the early presentation and better survival of Japanese patients with colorectal cancer in Hawaii (32, 33).

Colon cancer is difficult to cure when the disease has spread outside the large intestine. Given the high frequency of the C allele and if its stronger association with advanced disease were to be confirmed, this allele may be responsible for a sizable portion of the morbidity and mortality from colorectal cancer, especially in populations with low total folate intake. Moreover, if the subsite specificity of the association can be replicated, it will be interesting to see whether the folic acid fortification of the diet initiated in the United States in 1998 will result in a greater decrease in rates, if any, for colon than rectal cancer.

In conclusion, these data corroborate previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, especially at high levels of folate and low levels of ethanol intake. They also suggest that this effect may be specific to advanced colon cancer.

	Acknowledgments

 
We thank Jana Koerte and Jennifer Yamamoto for assistance with data analysis, and Wendy Chang, Annette Jones, and Ann Seifried for their help with genotyping.

	Footnotes

 
Grant support: National Cancer Institute, U.S. Department of Health and Human Services, grants R01 CA 63464 and R01 CA54281.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/15/04; revised 1/28/05; accepted 3/ 2/05.

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