When data were incomplete, study staff followed up by phone. , we restricted the study population to Caucasians (who comprised 97% of the original population) for a sample size of 510 cases and 604 controls. . (8) Patients (age 30–74 years) who were scheduled for colonoscopy between April 1991 and April 1994 were screened for eligibility and recruited prior to colonoscopy. ©2002 American Association for Cancer Research. Thymidylate synthase (TS) is a key enzyme in folate metabolism and the primary target of 5-fluorouracil.

(4 For the analysis of the TSER 28-bp repeat polymorphism, a fragment containing the repeats was amplified using primers TS forward primer: 5′-GTGGCTCCTGCGTTTCCCCC-3′ and TS reverse primer: 5′-GGCTCCGAGCCGGCCACAGGCATGGCGCGG-3′ Genomic DNA from lymphocytes was extracted using the PureGene kit (Gentra Systems, Inc., Minneapolis, MN). . Our findings raise questions regarding the molecular pathways linking folate metabolism to colorectal carcinogenesis, especially including whether folate is beneficial in the presence of all metabolic genotypes. No clear pattern was seen with the TS 1494del6 polymorphism. The human TS promoter region includes several mechanisms for gene regulation, including a cis-acting enhancer element , upon stratification by a relevant exposure (folate), an informative pattern emerged. Folate intake did not confound this association, nor did vitamin B12 confound the folate/TS association. . TS is also a target for major chemotherapeutic drugs, including 5-fluorouracil.

Eligibility criteria for both cases and controls were: (a) resident of Twin cities metropolitan area; (b) age 30–74 years; (c) English speaking; (d) no known genetic syndrome associated with colonic neoplasia; and (e) no history of cancer (except nonmelanoma skin cancer), adenomatous polyps, or inflammatory bowel disease. ,

Affected Drugs This conversion is essential for the provision of thymidine, a nucleotide needed for DNA synthesis and repair. As shown in Table 2

TS The 3′UTR polymorphism was analyzed by RFLP as described We also reported recently on a second TS polymorphism, a 6-bp deletion at bp 1494 in the 3′UTR that may be associated with decreased mRNA levels in colorectal tumors TS converts dUMP to dTMP, and it has been shown that folate deficiency can lead to uracil misincorporation associated with an increased risk of double-strand breaks

The associations with the TS polymorphism did not differ by intakes of vitamin B6, methionine, or alcohol (data not shown).

↵1 To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, Cancer Prevention Research Program, 1100 Fairview Avenue N, MP-900, Seattle, WA 98109-1024. , we observed a statistically significant gene-nutrient interaction with dietary folate intake: among individuals with the 3rpt/3rpt genotype, folate intake > 440 μg/day (highest tertile) versus ≤440 μg/day was associated with a 2-fold decreased risk [ORs 1 (ref; low intake) versus 0.5 (0.3–0.9; high intake)]. . Both variants were in Hardy-Weinberg equilibrium. Multivariate-adjusted odds ratios (ORs; 95% confidence interval) for TSER 2rpt/3rpt and 2rpt/2rpt compared with 3rpt/3rpt were 0.8 (0.6–1.2) and 0.9 (0.6–1.3), respectively.

The two polymorphisms were in linkage disequilibrium: among those with a TSER 3rpt/3rpt genotype, 29% were found to have the TS 6 bp/6 bp genotype and 26% the 0 bp/0 bp genotype; among individuals with a TSER 2rpt/2rpt genotype, these proportions were 73 and 3%, respectively (P < 0.001).

Thymidylate synthase is essential for purine synthesis required for DNA replication.

(12) Although an abundance of apurinic endonucleases efficiently repairs this damage, quantitative measurements show that abasic sites are present in cellular DNA, with a steady-state level of 5–10,000 lesions/cell/day 5-FU binds to an enzyme inside of cancer cells called thymidylate synthase and then exerts its anti-cancer effect on the cells. , we stratified the analysis further by MTHFR genotype (Table 3) (19) Briefly, cases and controls were recruited through a multiclinic private gastroenterology practice in metropolitan Minneapolis, Digestive Healthcare. (4

(9)

We observed a statistically significant gene environment interaction, with a decreased adenoma risk associated with high folate intakes among individuals with the TSER wild-type (3rpt/3rpt) genotype and the opposite association (increased risk with high folate intake) among individuals with lower TS expression (2rpt/2rpt). Edward Chu, Ashwin Gollerkeri, in Encyclopedia of Cancer (Second Edition), 2002. was only seen among those with the 3rpt/3rpt genotype (>3-fold). (20 ⇓ On the basis of biochemical models in pig liver, the cellular concentration of 5,10-methylene-THF regulates the flux of this metabolite into the pathways leading to nucleotide synthesis and methionine regeneration

It is recommended that this screening is accompanied by direct measurement of DPYD activity prior to 5-FU treatment in cancer patients. Privacy Policy. Conditions

. The TS 6-bp deletion polymorphism at bp 1494 in the 3′UTR was not associated significantly with risk of colorectal adenomas [compared with 6bp/6bp wild-type OR = 1 (reference): 6bp/0bp OR = 1.22 (0.93–1.61); 0 bp/0 bp OR = 1.13 (0.73–1.74)]. ⇓ These findings raise questions regarding the molecular pathways linking folate metabolism and colorectal carcinogenesis, including whether high folate is beneficial in the presence of all metabolic genotypes.

Multivariate adjustment included age, sex, body mass index (kg/m2), percentage of calories from fat, hormone replacement therapy (ever/never), and pack-years of smoking.

. Although one might expect results similar to those for the TSER polymorphism, because of linkage between the two polymorphisms, these findings illustrate that “imperfect” disequilibrium may result in different associations with disease phenotypes.

Patients with polyps showing invasive carcinoma were not included. Phone: (206) 667-7617; Fax: (206) 667-7850; E-mail: nulrich{at}fhcrc.org. Folate deficiency has been shown to increase several measures of DNA damage References, Blog

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Briefly, a fragment containing the 6-bp deletion was amplified using primers 5′-CAAATCTGAGGGAGCTGAGT-3′ and 5′-CAGATAAGTGGCAGTACAGA-3′ in a reaction containing 1 × GeneAmp buffer, 2.5 mm MgCl2, 150 mm deoxyribonucleotide triphosphates, 300 nm each primer, 1 unit of AmpliTaq DNA polymerase, and 100 ng of genomic DNA. 1

Genelex Team The cycling conditions were 1 cycle of 94°C for 5 min, 30 cycles of 94°C for 30 s, 58°C for 45 s, and 72°C for 45 s, and a final extension at 72°C for 5 min. . (21) The allele frequency of the TS 1494 6-bp deletion was 0.30 with 40% heterozygotes (6 bp/0 bp) and 10% homozygous variant (0 bp/0 bp). Other factors evaluated but not found to be confounders were waist:hip ratio, regular use of aspirin or nonsteroidal anti-inflammatory drugs (at least once/week versus never), hours of physical activity, and the dietary intake variables kcal, dietary fiber, vitamin B6, vitamin B12, and alcohol.
(10)

We observed a significant gene-nutrient interaction between the TSER polymorphism and folate intake: among 3rpt/3rpt individuals (greater expression), folate intake > 440 μg/day (highest tertile) versus ≤440 μg/day was associated with a 2-fold decreased risk [ORs 1.0 (reference group) versus 0.5 (0.3–0.9)]. 5-FU binds to an enzyme inside of cancer cells called thymidylate synthase and then exerts its anti-cancer effect on the cells. is a key enzyme in folate metabolism and catalyzes the conversion of dUMP to dTMP.

FAQs We here extend these findings to a common polymorphism in TS, which modifies risk depending on folate status (and possibly vitamin B-12 status). . was unexpected.

It may also have implications for the pharmacogenetics of antifolate drugs, such as 5-fluorouracil. Fluorouracil (5-FU) is one of the most successful and widely used chemotherapy drugs.

Cancer Research Online ISSN: 1538-7445
(6 The MTHFR C677T polymorphism was also not found to confound the associations. Although this test screens for the most frequent genetic variation that causes DPYD enzyme deficiency this does not rule out the possibility of a decrease in DPYD activity due to other factors or genetic variations. American Journal of Cancer ISSN: 0099-7374, Sign In to Email Alerts with your Email Address.

(15 ⇓ Thus, we hypothesize that the lower TS expression (2rpt/2rpt or 3rpt/2rpt genotypes) may have a “folate-sparing” effect that reduces risk of adenoma.

The study population and their dietary intakes have been described previously

Recruitment at all 10 sites was initiated at the time of scheduling with the intention of recruiting subjects with both patient and recruiter blind to the final diagnosis. , 13) However, all genotype combinations were observed. We investigated the risk of adenomas associated with all possible TSER/TS 1494del6 genotype combinations, and none of the risks was statistically different from 1 (with a TSER 3rpt/3rpt TS 6bp/6bp genotype as referent; data not shown).

(14) The indications for colonoscopy were not related to the TS genotype or to intakes of the nutrients investigated. At the colonoscopy visit, questionnaires were collected, blood was drawn, and the colonoscopy findings were recorded. Data suggest the potential association of methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and TS enhancer region (TSER) polymorphisms with recurrent implantation failure (RIF) risk in Korean patients. The amplified fragments were digested with DraI, and the products were separated on a 3% NuSieve agarose gel. , 5) Risk of colorectal polyps associated with the TSER polymorphism, stratified by folate (A) or vitamin B-12 (B) intake.

We investigated the role of TS polymorphisms in a case control study of adenomatous polyps (510 cases and 604 polyp-free controls). . The study protocol was approved by the internal review boards of the University of Minnesota, and each DH endoscopy site and written informed consent was given by each study participant.

(23)

This TSER is polymorphic, containing two or three 28-bp tandem repeats among Caucasian and Asian populations Our findings, however, suggest that the purine synthesis pathway may be a relevant mechanism linking folate metabolism to colorectal carcinogenesis. Association between the TSER polymorphism and adenomatous polyps—stratified by dietary intakes of folate and vitamin B12a. , and in vivo TS mRNA levels in tumor tissue were 3.6-fold lower among 2rpt/2rpt individuals compared with 3rpt/3rpt individuals



, 21) . Thus, depurination may be the major challenge the body faces on a continuous basis, and the provision of an adequate supply of purines may be an important prerequisite for repair. It is often used forof breast, colon, and skin cancer (three of the most frequently occurring cancers). Although the cell sizes are small, and the results should be considered exploratory, some trends are suggested: (a) the decrease in risk associated with high folate intakes was again confined to individuals with greater TS expression (3rpt/3rpt genotype), irrespective of MTHFR genotype; and (b) the previously reported increase in adenoma risk associated with low folate intake among individuals with the MTHFR TT genotype

, and selected characteristics are presented in Table 1

.

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