Mthfr (C677T) polymorphisms and stage III colon cancer: Response to therapy2

Wisotzkey, Jeffrey D.; Toman, Jeffrey; Bell, Theodore; Monk, John; Jones, David A.

doi:10.1016/s1084-8592(99)80034-4

Cited by 43 publications

(23 citation statements)

References 4 publications

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“…Therefore, we would expect that in the study population, patients who carry the 677TT genotype would be more sensitive to chemotherapy, in general, and more likely to have better survival, if the chemotherapy dose is appropriate. This hypothesis has been supported by one study conducted in colon cancer patients who received 5FU [15], although there was no association between survival from colon cancer and the 677T allele in another smaller study [21]. In our study, only women with the TT genotype and who had survived at least 2 years after an initial diagnosis of early stage disease had a possible increased survival, perhaps reflecting a better response to chemotherapy for those with localized disease.…”

Section: Discussionsupporting

confidence: 83%

MTHFR genotypes and breast cancer survival after surgery and chemotherapy: a report from the Shanghai Breast Cancer Study

Shrubsole

Shu

Ruan

et al. 2005

Breast Cancer Res Treat

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Methylenetetrahydrofolate reductase (MTHFR) regulates the intracellular folates pool for DNA synthesis and methylation. Sequence variations in MTHFR (nucleotides 677 (C-->T) and 1298 (A-->C)) result in allozymes with decreased activity. The 677TT genotype is associated with increased toxicity of methotrexate and increased clinical response to 5-fluorouracil in treatment of cancers including breast cancer. We evaluated MTHFR genotypes and breast cancer survival in a cohort of 1067 Chinese women diagnosed with breast cancer between 1996 and 1998 who received surgery and chemotherapy. Life table method was used to calculate 5-year survival rates. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) after adjusting for potential confounding factors. Median follow-up time was 5.2 years; 5-year survival was 84.6%. Sixty-six percent carried a 677T allele and 31% carried a 1298 C allele. We found that overall 5-year breast cancer survival did not differ significantly across all genotypes (85.3% for 677 CC and 83.8% for 677TT; 83.8% for 1298 AA and 79.1% for 1298 CC). However, carrying the 677T allele was associated with non-significant increased risk of death for subjects with late stage disease (stages III-IV) (HR=1.80, 95% CI: 0.79-4.14 for TT vs. CC, p for trend=0.15), particularly among those who had survived past the second year (HR=2.97, 95% CI: 1.10-7.98, p for trend=0.04). The A1298C genotypes were not significantly associated with risk of death. This study suggests that the MTHFR C677T polymorphisms may affect long-term survival from advanced breast cancer.

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Section: Discussionsupporting

confidence: 83%

MTHFR genotypes and breast cancer survival after surgery and chemotherapy: a report from the Shanghai Breast Cancer Study

Shrubsole

Shu

Ruan

et al. 2005

Breast Cancer Res Treat

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“…In two studies with, respectively, 45 and 51 colorectal cancer patients, the 677T genotype appeared to affect the folate pool. 44,45 In the latter study, no effect was seen of the 677T genotype on overall survival after oral 5-FU-based chemotherapy. 45 Contrary to this, in a study of 43 metastatic colorectal cancer patients receiving fluoropyrimidine-based chemotherapy, the presence of one or two mutant alleles was associated with increased tumour response.…”

Section: -Fluorouracilmentioning

confidence: 88%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Marchand

Wilkens²,

Kolonel³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

128

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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. (Cancer Epidemiol Biomarkers Prev 2005;14(5):1198 -203)

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Mthfr (C677T) polymorphisms and stage III colon cancer: Response to therapy2

Cited by 43 publications

References 4 publications

MTHFR genotypes and breast cancer survival after surgery and chemotherapy: a report from the Shanghai Breast Cancer Study

MTHFR genotypes and breast cancer survival after surgery and chemotherapy: a report from the Shanghai Breast Cancer Study

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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

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