***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Background : Systematic genome-wide reductions of methylated cytosine ( 5-mC ) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis , possibly as a consequence of inadequate folate intake . Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies . Methods : To minimize disease- and /or treatment-related effects , we studied leukocyte 5-mC levels in prospect ively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate , Lung , Colorectal , and Ovarian ( PLCO ) Cancer Screening Trial .  Leukocyte 5-mC level was determined by a high-pressure liquid chromatography (HPLC)/t and em mass spectrometry method and expressed as the relative amount of methyl to total cytosine residues , or % 5-mC. We estimated the association between colorectal cancer risk and % 5-mC categories by computing ORs and 95 % confidence intervals ( CI ) through logistic regression modeling . Results : We observed no dose-dependent association between colorectal cancer and % 5-mC categories ( lowest vs. highest tertile : OR , 1.14 ; 95 % CI , 0.80–1.63 ; Ptrend = 0.51 ) . However , among subjects whose 5-mC levels were at the highest tertile , we observed an inverse association between natural folate intake and colorectal cancer ( highest tertile of natural folate vs. lowest : OR , 0.35 ; 95 % CI , 0.17–0.71 ; Ptrend = 0.003 ; Pinteraction = 0.003 ) . Conclusions : This prospect i ve investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk but a suggestive risk modification between 5-mC level and natural folate intake . Impact : Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome . Cancer Epidemiol Biomarkers Prev ; 21(11 ) ; 2014–21 . © 2012 AACR BACKGROUND Folic acid , vitamin B(6 ) , and vitamin B(12 ) act in concert in the one-carbon metabolism and may protect against colorectal neoplasia . We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma . METHODS The Women 's Antioxidant and Folic Acid Cardiovascular Study was a r and omized , double-blind , placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005 . Participants were r and omly assigned to receive a combination pill of folic acid ( 2.5 mg ) , vitamin B(6 ) ( 50 mg ) , and vitamin B(12 ) ( 1 mg ) or placebo . This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up . We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors . All statistical tests were two-sided . RESULTS The risk of colorectal adenoma was similar among participants receiving treatment ( 24.3 % , 180 of 741 participants ) vs placebo ( 24.0 % , 175 of 729 participants ) ( multivariable adjusted relative risk = 1.00 , 95 % confidence interval = 0.83 to 1.20 ) . Treatment was not associated with the risk of adenoma when data were analyzed by subsite , size , stage , and the number of adenomas . There was no statistically significant effect modification by alcohol intake , history of cancer or adenoma , or baseline plasma levels or intakes of folate , vitamin B(6 ) , or vitamin B(12 ) . CONCLUSION Our results indicate no statistically significant effect of combined folic acid , vitamin B(6 ) , and vitamin B(12 ) treatment on colorectal adenoma among women at high risk for cardiovascular disease BACKGROUND & AIMS Folate intake has been inversely associated with  colorectal cancer risk in several prospect i ve epidemiologic studies . However , no study fully assessed the influence of the high levels of folate that are frequently consumed in the United States as a result of m and atory folate fortification , which was fully implemented in 1998 , and the recent increase in use of folate-containing supplements . There is evidence that consumption of high levels of folic acid , the form of folate used for fortification and in supplements , has different effects on biochemical pathways than natural folates and might promote carcinogenesis . METHODS We investigated the association between  folate intake  and colorectal cancer among 43,512 men and 56,011 women in the Cancer Prevention Study II ( CPS-II ) Nutrition Cohort ; 1023 were diagnosed with colorectal cancer between 1999 and 2007 , a period entirely after folate fortification began . Cox proportional hazards regression was used to calculate multivariate hazards ratios ( RR ) and 95 % confidence interval ( CI ) . RESULTS Intake of high levels of natural folate  ( RRQ5vsQ1=0.86 ; 95 % CI : 0.70 - 1.06 ; P trend=.12 ) or folic acid ( RRQ5vsQ1=0.84 ; 95 % CI : 0.68 - 1.03 ; P trend=.06 ) were not significantly associated with risk of colorectal cancer . Total folate intake was significantly associated with lower risk ( RRQ5vsQ1=0.81 ; 95 % CI : 0.66 - 0.99 ; P trend=.047 ) . CONCLUSIONS Intake of high levels of total folate reduces risk of colorectal cancer ; there is no evidence that dietary fortification or supplementation with this vitamin increases colorectal cancer risk Background and aims Although critical for methylation reactions , how dietary folate and B vitamins affect global DNA methylation level in colorectal cancers is currently unknown . Long interspersed nucleotide element-1 ( LINE-1 ) is an emerging indicator of genome-wide DNA methylation level that has previously been linked to colon cancer survival . Methods We examined the association between dietary intake of folate , alcohol and B vitamins and LINE-1 hypomethylation in 609 incident colon cancers , utilising the data base of two independent prospect i ve cohort studies . Results Participants with ≥400 μg folate intake per day were significantly less likely to develop LINE-1 hypomethylated colon cancers than those reporting < 200 μg of folate intake per day ( RR=0.57 , 95 % CI=0.36 to 0.91 for < 55 % LINE-1 methylated colon tumours ; RR=0.74 , 95 % CI=0.51 to 1.06 for 55–64 % LINE-1 methylated colon tumours ; and RR=1.08 , 95 % CI=0.66 to 1.75 for ≥65 % LINE-1 methylated tumours ; Pinteraction=0.01 ) . By contrast , high alcohol consumption conferred a higher risk of LINE-1 hypomethylated cancers ( ≥15 g alcohol per day versus none , RR=1.67 , 95 % CI=1.04 to 2.67 for < 55 % LINE1 methylated tumours ; and RR=1.55 , 95 % CI=1.10 to 2.18 for 55–64 % LINE-1 methylated tumours ) but had no association with ≥65 % LINE-1 methylated tumours ( RR=1.06 , 95 % CI=0.69 to 1.62 ) . High intakes of vitamin B6 , B12 or methionine were not significantly associated with colon cancers , regardless of LINE-1 methylation level . Conclusion The influence of dietary folate intake and alcohol consumption on colon cancer risk differs significantly according to tumoral LINE-1 methylation level CONTEXT Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine . OBJECTIVE To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled , 2-factor , phase 3 , r and omized clinical trial conducted at 9 clinical centers between July 6 , 1994 , and October 1 , 2004 . Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma . INTERVENTION Participants were r and omly assigned in a 1:1 ratio to receive 1 mg/d of folic acid ( n = 516 ) or placebo ( n = 505 ) , and were separately r and omized to receive aspirin ( 81 or 325 mg/d ) or placebo . Follow-up consisted of 2 colonoscopic surveillance cycles ( the first interval was at 3 years and the second at 3 or 5 years later ) . MAIN OUTCOME MEASURES The primary outcome measure was occurrence of at least 1 colorectal adenoma . Secondary outcomes were the occurrence of advanced lesions ( > or = 25 % villous features , high- grade dysplasia , size > or = 1 cm , or invasive cancer ) and adenoma multiplicity ( 0 , 1 - 2 , or > or =3 adenomas ) . RESULTS During the first 3 years , 987 participants ( 96.7 % ) underwent colonoscopic follow-up , and the incidence of at least 1 colorectal adenoma was 44.1 % for folic acid ( n = 221 ) and 42.4 % for placebo ( n = 206 ) ( unadjusted risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.90 - 1.20 ; P = .58 ) . Incidence of at least 1 advanced lesion was 11.4 % for folic acid ( n = 57 ) and 8.6 % for placebo ( n = 42 ) ( unadjusted RR , 1.32 ; 95 % CI , 0.90 - 1.92 ; P = .15 ) . A total of 607 participants ( 59.5 % ) underwent a second follow-up , and the incidence of at least 1 colorectal adenoma was 41.9 % for folic acid ( n = 127 ) and 37.2 % for placebo ( n = 113 ) ( unadjusted RR , 1.13 ; 95 % CI , 0.93 - 1.37 ; P = .23 ) ; and incidence of at least 1 advanced lesion was 11.6 % for folic acid ( n = 35 ) and 6.9 % for placebo ( n = 21 ) ( unadjusted RR , 1.67 ; 95 % CI , 1.00 - 2.80 ; P = .05 ) . Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers . There was no significant effect modification by sex , age , smoking , alcohol use , body mass index , baseline plasma folate , or aspirin allocation . CONCLUSIONS Folic acid at 1 mg/d does not reduce colorectal adenoma risk . Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00272324 BACKGROUND A higher folate intake is associated with a decreased colorectal cancer risk in observational studies , but recent evidence suggests that excessive folate supplementation may increase colorectal cancer risk in some individuals . Therefore , m and atory folic acid fortification of grain products in the United States may have unintended negative consequences . OBJECTIVE We examined the association between folate intake and colorectal cancer risk , including 8.5 y of postfortification follow-up . DESIGN We examined the association between  folate intake and colorectal cancer in the NIH-AARP Diet and Health Study -a US cohort study of 525,488 individuals aged 50 - 71 y initiated in 1995 - 1996 .  Dietary , supplemental , and total folate intakes  were calculated for the pre- and postfortification periods ( before and after 1 July 1997 ) based on a baseline food-frequency question naire . HRs and 95 % CIs were calculated by using multivariable Cox proportional hazards regression models . RESULTS During follow-up through 31 December 2006 ( mean follow-up : 9.1 y ) , 7212 incident colorectal cancer cases were identified . In the postfortification analysis ( 6484 cases ) , a higher total  folate intake was associated with a decreased colorectal cancer risk ( HR for ≥900 compared with < 200 μg 
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Findings of present study highlight the importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed