• MTHFR polymorphisms
• A1298C
• C677T
• Case–control study
• Digestive system cancer

• 2022YFC2009600 the National Key Research and Development Program
• 2022YFC2009601 the National Key Research and Development Program
• XMHT20220104055 the Department of Science and Technology of Guangdong Province, and the Development and Reform Commission of Shenzhen Municipality
• 2018ZX09739010 National Key Research and Development Program of China
• 2018ZX09301034003 National Key Research and Development Program of China
• 2020B121202010 the Department of Science and Technology of Guangdong Province, Guangdong Key Laboratory of H-type Hypertension and Stroke Precision Prevention Research and Development Enterprise
• JSGG20180703155802047 Science, Technology and Innovation Committee of Shenzhen
• JSGG20201103153807021 Science, Technology and Innovation Committee of Shenzhen
• KCXFZ20211020163801002 Science, Technology and Innovation Committee of Shenzhen

• Breast cancer
• carcinogenic
• colorectal cancer
• folate
• folic acid
• lung cancer
• prostate cancer

• Humans
• Folic Acid/therapeutic use
• Neoplasms/drug therapy
• Dietary Supplements
• Multicenter Studies as Topic

• African-American
• Hispanic
• breast cancer
• exome
• health disparity
• variants

• U54 MD007598 NIMHD NIH HHS

• DPYD
• MTHFR
• TYMS
• adverse effects
• colorectal cancer
• fluoropyrimidines
• pharmacogenetics
• polymorphisms

The two common methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677G>A and 1298A>C may have been affecting 5-FU toxicity in cancer patients for decades. Drug efficacy has also been shown by previous studies to be affected. In this study, we investigated the effects of these polymorphisms on 5-FU hematological toxicity and treatment efficacy, to provide enhanced pharmacological treatment for cancer patients.

This is a retrospective study involving 52 Thai colorectal cancer patients who were treated with 5-FU based therapy, using TaqMAN real-time PCR to genotype the MTHFR polymorphisms (677G>A and 1298A>C). The toxicity and response rate were assessed using standardized measures.

Neutropenia was significantly more likely to be experienced (P=0.049, OR=7.286, 95% CI=0.697-76.181) by patients with the MTHFR 677G>A polymorphism, in the same way as leukopenia (P =0.036, OR=3.333, 95%CI=2.183-5.090) and thrombocytopenia (P<0.001, OR=3.917, 95%CI=2.404-6.382). The MTHFR 1298A>C polymorphism had no statistical association with hematological toxicity in 5-FU treatment. The response rate to 5-FU was not significantly affected by these two polymorphisms.

The MTHFR polymorphism 677G>A is a significant risk factor for developing leukopenia, neutropenia and thrombocytopenia as toxic effects of 5-FU therapy in cancer patients. Therefore, patients receiving 5-FU-based therapy should be aware of their polymorphisms as one risk factor for experiencing severe toxicity.

• 5-fluorouracil
• Hedgehog pathway
• JAK/STAT pathway
• NF-κB pathway
• Notch pathway
• Wnt pathway

Tumor initiation and progression are sustained by the ability of the cancer cell to reshape its metabolism in a way that favors cell proliferation and survival. Recently, it was shown that heme metabolism contributes to metabolic adaptation of tumor cell and that interfering with heme homeostasis reduces tumor cell growth. Here, we show that the alteration of heme metabolism, either by RNA-interference or pharmacological approaches, increases the sensitivity of tumor cell lines to the antitumor agent metformin. These findings strengthen the concept of targeting heme metabolism to counteract tumor progression.

Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal role in the control of metabolic adaptations that sustain cancer cell proliferation. Recently, we demonstrated the existence of a functional axis between the heme synthetic enzyme ALAS1 and the heme exporter FLVCR1a exploited by cancer cells to down-modulate oxidative metabolism. In colorectal cancer cell lines, the inhibition of heme synthesis-export system was associated with reduced proliferation and survival. Here, we aim to assess whether the inhibition of the heme synthesis-export system affects the sensitivity of colorectal cancer cells to metformin. Our data demonstrate that the inhibition of this system, either by blocking heme efflux with a FLVCR1a specific shRNA or by inhibiting heme synthesis with 5-aminolevulinic acid, improves metformin anti-proliferative effect on colorectal cancer cell lines. In addition, we demonstrated that the same effect can be obtained in other kinds of cancer cell lines. Our study provides an in vitro proof of concept of the possibility to target heme metabolism in association with metformin to counteract cancer cell growth.

Previous studies have revealed the critical role of methylene tetrahydrofolate reductase (MTHFR) polymorphisms in response to high-dose methotrexate (MTX)-induced toxicity in osteosarcoma patients. However, the conclusions remain controversial. In this setting, we performed a meta-analysis to determine their association more precisely.

Eligible studies were searched and screened in PubMed, Web of Science, Cochrane Library, Clinical-Trials.gov, Embase, and China National Knowledge Infrastructure (CNKI) following specific inclusion and exclusion criteria. The required information was retrieved and collected for subsequent meta-analysis. Association between MTHFR polymorphism and MTX toxicity was evaluated by odds ratios (ORs).

Seven studies containing 585 patients were enrolled and analyzed in this meta-analysis. Overall, the MTX related grade 3-4 liver toxicity was significantly associated with MTHFR rs1801133 allele (T vs. C: OR=1.61, 95%CI=1.07-2.42, P=0.024), homozygote (TT vs. CC: OR=2.11, 95%CI=1.06-4.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in Asian population. Meanwhile, close associations between MTX mediated grade 3-4 mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P<0.001), homozygote comparison (TT vs. CC: OR=4.07, 95%CI=1.76-9.38, P=0.001), heterozygote comparison (TC vs. CC: OR=2.55, 95%CI=1.20-5.42, P=0.015), recessive genetic model (TT vs. TC/CC: OR=2.09, 95%CI=1.19-3.67, P=0.010), and dominant genetic model (TT/TC vs. CC: OR=2.97, 95%CI=1.48-5.96, P=0.002). Additionally, kidney toxicity was corelated with the heterozygote comparison (TC vs. CC: OR=2.63, 95%CI=1.31-5.29, P=0.007) of rs1801133 polymorphism.

The MTHFR rs1801133 polymorphism was significantly associated with severer liver toxicity induced by high-dose MTX treatment in the Asian population. In the meantime, patients with MTHFR rs1801133 polymorphism were predisposed to MTX- related mucositis.

• MTHFR
• methotrexate
• osteosarcoma
• polymorphism
• toxicity

• adverse drug reaction
• pemetrexed (PEM)
• pharmacogenomics
• survival

• 5-FU-Resistance
• Colorectal cancer therapy
• Mouse xenograft model
• Pharmacokinetic properties
• S1PR2 antagonists

• Case-Control Studies
• Colonic Neoplasms
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Fluorouracil
• Genetic Predisposition to Disease
• Genotype
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Polymorphism, Single Nucleotide/genetics

• Esophageal cancer
• artificial intelligence
• imaging mass spectrometry
• machine learning
• metabolic response evaluation
• patient stratification
• spatial metabolomics
• tumor regression grading

• MTHFR
• breast cancer
• gastric cancer
• glioma
• polymorphism

• Brain Neoplasms/ethnology
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Breast Neoplasms/ethnology
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• DNA Methylation
• Female
• Folic Acid/metabolism
• Genetic Predisposition to Disease
• Glioma/ethnology
• Glioma/genetics
• Glioma/metabolism
• Humans
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Methylenetetrahydrofolate Reductase (NADPH2)/metabolism
• Polymorphism, Single Nucleotide
• Stomach Neoplasms/ethnology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism

• MTHFR rs1801133
• gastric cancer
• polymorphism
• risk

• DNA methylation
• MTHFR genes polymorphism
• malignancies
• one-carbon metabolism pathway
• vitamin B9

• 5-FU
• Colorectal cancer
• Drug resistance
• Pharmacogenomics

• 5-fluorouracil
• 5-fluorouracil pro-drugs
• Chemoresistance
• Colorectal cancer
• Drug resistance
• Oral fluoropyrimidines

• CDKN2A/B gene
• MTHFR gene
• breast cancer
• menarche
• menopause status
• polymorphism

• cytochrome p450
• metabolizer
• pharmacogenomics
• ultrarapid

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of MTHFR polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were applied to assess the strength of association. A total of 2118 colorectal cancer patients from 21 studies were included in the meta-analysis. Overall, there was no significant association between MTHFR C677T (rs1801133) or A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (allele model, dominant model, and recessive model) and stratification analysis, except for the retrospective study subgroup in the dominant model of MTHFR C677T and the “5-Fu + FA” treatment group in the allele contrast of MTHFR A1298C. No or moderate heterogeneity was observed in all genetic models. This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the clinical response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

• MTHFR
• chemotherapy response
• fluoropyrimidine
• meta-analysis
• polymorphism

• Capecitabine
• Fluropyrimidines
• Gastrointestinal cancer
• S-1, TAS-102
• Thymidylate synthase

• Administration, Oral
• Antimetabolites, Antineoplastic/pharmacology
• Antimetabolites, Antineoplastic/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/metabolism
• Clinical Trials as Topic
• Dihydrouracil Dehydrogenase (NADP)/metabolism
• Drug Combinations
• Drug Resistance, Neoplasm
• Drug Synergism
• Fluorouracil/pharmacology
• Fluorouracil/therapeutic use
• Folic Acid Antagonists/pharmacology
• Folic Acid Antagonists/therapeutic use
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/pathology
• Humans
• Molecular Targeted Therapy/methods
• Molecular Targeted Therapy/trends
• Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Pyrrolidines
• Thymidine Phosphorylase/metabolism
• Thymidylate Synthase/antagonists & inhibitors
• Thymidylate Synthase/metabolism
• Thymine
• Trifluridine/pharmacology
• Trifluridine/therapeutic use
• Uracil/analogs & derivatives
• Uracil/pharmacology
• Uracil/therapeutic use

In the present study, we aimed to retrospectively analyze the correlation between toxicity of pemetrexed (PEM) chemotherapy and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC).

We used polymerase chain reaction, gene scanning, and restriction fragment length polymorphism to analyze MTHFR C677T in 51 patients with advanced non-sq NSCLC. The patients received chemotherapies with single-agent PEM (monotherapy group) or with PEM combined with cisplatin (joint group). The correlation between MTHFR C677T polymorphisms and chemotherapy efficacy/toxicity was also assessed.

There were 40 patients in the monotherapy group and 11 patients in the joint group. Among the 40 patients received single-agent PEM chemotherapy, those with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue compared to patients with the with wild-type genotype CC (all P<0.05). However, polymorphisms of MTHFR C677T were not significantly associated with other adverse events and clinical outcomes.

Compared with genotype CC (the wild type), patients with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue. Therefore, the MTHFR C677T polymorphism could be a predictive factor for leukopenia, neutropenia, nausea, and fatigue toxicities in non-sq NSCLC patients treated with single-agent PEM.

• DNA sequencing
• actionable target
• colorectal cancer
• gene variants
• pharmacogenomics
• precision medicine

• chemotherapy
• colorectal cancer
• depth of response
• early tumor shrinkage
• polymorphism

The aim of this study is to clarify the relationship between recurrence risk of breast cancer and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms.

Breast cancer patients who had undergone surgery in Gaziantep University Oncology Hospital between June 2005 and June 2012 were followed-up and retrospectively enrolled in this study. Blood samples were collected from all patients to assess MTHFR C677T polymorphisms. Stage according to tumor–node–metastasis system, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 status, grade of disease, menopausal status, and administered chemotherapy or hormonal therapy were recorded. Effects of these parameters on recurrence risk were evaluated using univariate analysis and multivariate binary logistic regression model.

Association of MTHFR C677T polymorphisms with recurrence risk was evaluated in 298 patients whose median age was 47 years (range: 21–79 years). In all patients, age (odds ratio [OR] =0.953, P=0.005) and N3 lymph node status (OR =6.293, P=0.001) were found to affect the recurrence risk. While MTHFR homozygote genotype did not have an effect on recurrence risk in all patients, increased risk was observed in lymph node-positive subgroup (OR =4.271; 95% CI 1.515–12.023; P=0.006). Adjusting for age, tumor size (T), and node status (N), MTHFR homozygote genotype had more statistically significant risk for recurrence (OR =3.255; 95% CI 1.047–10.125; P=0.041).

MTHFR TT genotype was found to be associated with increased recurrence risk in patients with lymph node-positive breast cancer.

• MTHFR
• breast cancer
• methylenetetrahydrofolate reductase
• recurrence risk
• rs9651118 polymorphism

• ATP Binding Cassette Transporter, Subfamily B/genetics
• Adult
• Aged
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Chemotherapy, Adjuvant
• Cytochrome P-450 CYP2C19/genetics
• Female
• Genotype
• Humans
• Logistic Models
• Middle Aged
• Multifactor Dimensionality Reduction
• Polymorphism, Single Nucleotide

• Chemotherapy
• Colorectal cancer
• GSTP1
• Gastric cancer
• Meta-analysis
• Polymorphism

Association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism and DNA methylation, and breast cancer risk are inconsistent. We investigated in a case-control study, possible effect of the common MTHFR C677T polymorphism on breast cancer risk in a sample of Iranian patients.

The study subjects comprised of 123 breast cancer cases and 110 cancer-free control, who were matched for age and body mass index (BMI). C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Lipid profile was measured in all subjects by standard method.

The genotypes distributions (CC, CT, and TT) were 55.3, 39, and 5.7% in breast cancer cases and 51.8, 44.5, and 3.6% in controls. Chi square analysis revealed that there was no significant association between breast cancer risk and MTHFR genotypes and alleles. Additionally, no significant association was observed between C677T genotypes and biochemistry parameters. A multinomial logistic regression model with MTHFR genotypes, lipid profiles, BMI and age as covariates revealed that there is no significant association between MTHFR genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer.

Our findings do not support the hypothesis that genetic variation in the MTHFR C677T polymorphism is implicated in the breast cancer risk in a sample of Iranian patients.

• Brest Cancer
• MTHFR C677T polymorphism
• PCR-RFLP

• colon adenocarcinoma
• colon cancer
• resistance

Genetic polymorphisms have a potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy, but we have not found any pharmacogenomics information regarding minorities, such as the Miao ethnic group. Our study aimed to screen numbers of the Miao ethnic group for genotype frequencies of VIP variants and to determine differences between the Miao and other human populations worldwide.

In this study, we genotyped 66 Very Important Pharmacogene (VIP) variants selected from PharmGKB in 98 unrelated, healthy Miao individuals from the Guizhou province and compared our data with 12 other populations, including 11 populations from the HapMap data set and Xi’an Han Chinese.

Using the χ² test, we found that the allele frequencies of the VDR rs1544410 and VKORC1 (rs9934438) variants in the Miao population are quite different from that in other ethnic groups. Furthermore, we found that genotype frequencies of rs1801133 (MTHFR) in the 13 selected populations are significantly different. Population structure and F-statistics (Fst) analysis show that the genetic background of the Miao is relatively close to that of Chinese in metropolitan Denver, CO, USA (CHD).

Our results help complete the information provided by the pharmacogenomics database of the Miao ethnic group and provide a theoretical basis for safer drug administration, which may be useful for diagnosing and treating diseases in this population.

• MTHFR
• Non-small cell lung cancer
• Pemetrexed monotherapy
• Polymorphism
• TS

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Middle Aged
• Neoplasm Staging
• Pemetrexed/therapeutic use
• Polymerase Chain Reaction
• Polymorphism, Restriction Fragment Length
• Polymorphism, Single Nucleotide/genetics
• Prognosis
• Retrospective Studies
• Survival Rate
• Thymidylate Synthase/genetics

• Antimetabolites, Antineoplastic/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Female
• Humans
• Methotrexate/therapeutic use
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• NAD(P)H Dehydrogenase (Quinone)/genetics
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Treatment Outcome

Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations.

In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016).

Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.

• Anticancer Drug
• Cell Cycle
• Colon Cancer
• E3 Ubiquitin Ligase
• G1 Maintenance
• Microarray
• RFPL4A

• Antineoplastic Agents/administration & dosage
• Apoptosis/drug effects
• Cell Cycle/drug effects
• Cell Cycle/genetics
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• G1 Phase/drug effects
• G1 Phase/genetics
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Microarray Analysis
• Ubiquitin-Protein Ligases/biosynthesis

Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance.

• 5-fluorouracil
• Resistance
• Transporters
• Metabolic enzyme
• Signaling pathway
• Stromal factors
• MicroRNA
• Proteomic investigation

• Animals
• Antimetabolites, Antineoplastic/metabolism
• Antimetabolites, Antineoplastic/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Cycle/drug effects
• Cell Cycle/genetics
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• DNA Repair/drug effects
• DNA Repair/genetics
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Fluorouracil/metabolism
• Fluorouracil/therapeutic use
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proteomics/methods

• 5-fluorouracil
• MTHFR polymorphism
• clinical trial
• folate
• pharmacogenetics
• rectal cancer
• survival
• toxicity

• Adult
• Aged
• Aged, 80 and over
• Disease-Free Survival
• Female
• Fluorouracil/administration & dosage
• Folic Acid
• Genetic Association Studies
• Genetic Predisposition to Disease
• Glycine Hydroxymethyltransferase/genetics
• Humans
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Middle Aged
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Rectal Neoplasms/genetics
• Rectal Neoplasms/pathology
• Reduced Folate Carrier Protein/genetics
• Thymidylate Synthase/genetics

• U10 CA046113 NCI NIH HHS
• CA58882 NCI NIH HHS
• U10 CA32102 NCI NIH HHS
• R01 CA105145 NCI NIH HHS
• U10 CA032102 NCI NIH HHS
• N01 CA038926 NCI NIH HHS
• U10 CA180888 NCI NIH HHS
• U10 CA180819 NCI NIH HHS
• U10 CA058882 NCI NIH HHS
• CA46113 NCI NIH HHS
• U10 CA038926 NCI NIH HHS

• A1298C
• Breast cancer
• Folate
• Meta-analysis
• Methylenetetrahydrofolate reductase
• Polymorphism

We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.

The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5′-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3′-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations’ results were correlated with disease control rate, progression-free survival (PFS) and overall survival.

Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.

The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.

• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/mortality
• DNA-Binding Proteins/genetics
• Endonucleases/genetics
• Female
• Glutamates/administration & dosage
• Guanine/administration & dosage
• Guanine/analogs & derivatives
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/mortality
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Middle Aged
• Pemetrexed
• Platinum/administration & dosage
• Polymorphism, Single Nucleotide
• Proportional Hazards Models
• Retrospective Studies
• Thymidylate Synthase/genetics

• colorectal cancer
• folate levels
• gene polymorphisms

Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.

569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).

Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6^th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7^th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.

The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6^th or 7^th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification.

• 9,10-Dimethyl-1,2-benzanthracene
• Adenocarcinoma/chemically induced
• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Animals
• Dietary Supplements/adverse effects
• Disease Progression
• Female
• Folic Acid/adverse effects
• Gene Expression/drug effects
• Humans
• Mammary Neoplasms, Experimental/chemically induced
• Mammary Neoplasms, Experimental/genetics
• Mammary Neoplasms, Experimental/metabolism
• Mammary Neoplasms, Experimental/pathology
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Poly(ADP-ribose) Polymerases
• Rats
• Rats, Sprague-Dawley
• Receptor, ErbB-2
• Tumor Burden/drug effects
• bcl-2-Associated X Protein