DPYD

Gene Summary

Gene:DPYD; dihydropyrimidine dehydrogenase
Aliases: DHP, DPD, DHPDHASE
Location:1p22
Summary:The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:dihydropyrimidine dehydrogenase [NADP(+)]
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Dihydrouracil Dehydrogenase (NADP)
  • Deoxycytidine
  • Young Adult
  • Triple Negative Breast Cancer
  • Breast Cancer
  • Chromosome 1
  • Antimetabolites, Antineoplastic
  • Case-Control Studies
  • Mutation
  • Uracil
  • RTPCR
  • Thrombocytopenia
  • DNA Sequence Analysis
  • Transcription Factors
  • Staging
  • Thymidylate Synthase
  • Camptothecin
  • Adenocarcinoma
  • Drug Resistance
  • Dihydropyrimidine Dehydrogenase Deficiency
  • Antineoplastic Agents
  • Messenger RNA
  • Polymerase Chain Reaction
  • Genotype
  • Genetic Variation
  • Polymorphism
  • Tumor Burden
  • Exons
  • Fluorouracil
  • Pharmacogenetics
  • Turkey
  • Promoter Regions
  • Severity of Illness Index
  • Colonic Neoplasms
  • Vomiting
  • Protein Conformation
  • Colorectal Cancer
  • Stomach Cancer
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Risk Factors
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DPYD (cancer-related)

Ramos-Díaz R, Gutiérrez-Nicolás F, Nazco-Casariego GJ, et al.
Validation of a fast and low-cost alkaline lysis method for gDNA extraction in a pharmacogenetic context.
Cancer Chemother Pharmacol. 2015; 75(5):1095-8 [PubMed] Related Publications
PURPOSE: Translation of pharmacogenetic findings from the research laboratory to the clinical practice demands simple and efficient procedures. In this sense, we evaluated the suitability of a modified protocol for genomic DNA extraction based on alkaline lysis of cells.
METHODS: Dried blood samples were obtained from 48 patients diagnosed with colorectal cancer. A total of 11 mutations in the dihydropyrimidine dehydrogenase gene and related to 5-fluorouracil toxicity were searched by amplicon sequencing and real-time PCR with fluorescent probes.
RESULTS: Genomic DNA extracted with the alkaline lysis method, both from dried blood samples and buccal swabs, fulfilled the quality requirements of the two genotyping methods assayed, which yielded 100 % concordant results for 11 genetic variants with relevance to cancer chemotherapy.
CONCLUSIONS: The assessed protocol has shown to be a very fast and economical approach to perform genetic analyses in the clinical laboratory for pharmacological purposes.

Grimminger PP, Maus MK, Bergenthal J, et al.
Prognostic impact of blood biomarkers TS and DPD in neoadjuvant-treated esophageal cancer patients.
Anticancer Res. 2015; 35(3):1297-302 [PubMed] Related Publications
BACKGROUND/AIM: The prognostic value of TS (thymidylate synthase) and DPD (dihydropyrimidine dehydrogenase) RNA expression in the blood of patients with esophageal cancer is not known. The aim of the present study was to evaluate the significance of these molecular alterations in the blood as a prognostic marker for patients with neoadjuvant-treated esophageal cancer.
PATIENTS AND METHODS: A total of 29 patients with locally advanced esophageal cancer (cT3-T4, Nx, M0) were enrolled in this prospective study. All patients received neoadjuvant chemoradiation followed by a transthoracic resection (curative transthoracic en bloc esophagectomy, RO). Peripheral blood samples were drawn before initiation of therapy. The analysis was performed using quantitative real-time-polymerase chain reaction (RT-PCR). The histomorphological regressions grading after neoadjuvant therapy was defined as follows: major response (MaR)=less than 10% vital tumor tissue, minor response (MiR)=more than 10% vital tumor tissue.
RESULTS: Nineteen out of 29 patients (65.5%) had a MiR and 10 (34.5%) had a MaR. The median survival of patients was 2.08 years (range=0.15-4.53). Among the tested genes, the RNA expression of TS was significantly associated with prognosis of patients. Patients with TS expression above 0.78 had a median survival of 1.1 years (range=0.21-3.96) compared to 2.6 years (range=0.15 to 4.53) in patients with TS expression lower than 0.78 (p=0.031, log rank test). There was no association between clinical variables (e.g., tumor stage, gender, age, etc.) and the RNA expression of TS in the serum.
CONCLUSION: The RNA expression of TS in the blood is a potential prognostic marker in patients with neoadjuvant-treated esophageal cancer. The significance of these molecular alterations as non-invasive prognostic marker for esophageal cancer should be evaluated in prospective studies.

Joerger M, Huitema AD, Boot H, et al.
Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy.
Cancer Chemother Pharmacol. 2015; 75(4):763-72 [PubMed] Related Publications
PURPOSE: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies.
METHODS: We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests.
RESULTS: Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group.
CONCLUSIONS: Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.

Kalia M
Biomarkers for personalized oncology: recent advances and future challenges.
Metabolism. 2015; 64(3 Suppl 1):S16-21 [PubMed] Related Publications
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells and oncology is a branch of medicine that deals with tumors. The last decade has seen significant advances in the development of biomarkers in oncology that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as we begin to understand the complex mechanisms that transform a normal cell into an abnormal one. These discoveries have fueled the development of novel drug targets and new treatment strategies. The standard of care for patients with advanced-stage cancers has shifted away from an empirical treatment strategy based on the clinical-pathological profile to one where a biomarker driven treatment algorithm based on the molecular profile of the tumor is used. Recent advances in multiplex genotyping technologies and high-throughput genomic profiling by next-generation sequencing make possible the rapid and comprehensive analysis of the cancer genome of individual patients even from very little tumor biopsy material. Predictive (diagnostic) biomarkers are helpful in matching targeted therapies with patients and in preventing toxicity of standard (systemic) therapies. Prognostic biomarkers identify somatic germ line mutations, changes in DNA methylation, elevated levels of microRNA (miRNA) and circulating tumor cells (CTC) in blood. Predictive biomarkers using molecular diagnostics are currently in use in clinical practice of personalized oncotherapy for the treatment of five diseases: chronic myeloid leukemia, colon, breast, lung cancer and melanoma and these biomarkers are being used successfully to evaluate benefits that can be achieved through targeted therapy. Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and gastrointestinal tumors; anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALk fusion; HER2/neu blockage in HER2/neu-positive breast cancer; and epidermal growth factor receptors (EGFR) inhibition in EGFR-mutated lung cancer. This review presents the current state of our knowledge of biomarkers in five selected cancers: chronic myeloid leukemia, colorectal cancer, breast cancer, non-small cell lung cancer and melanoma.


Metabolic rewiring is required for epithelial-mesenchymal transition.
Cancer Discov. 2014; 4(11):OF20 [PubMed] Related Publications
Expression of metabolic genes such as dihydropyrimidine dehydrogenase (DPYD) is essential for EMT.

Koumarianou A, Tzeveleki I, Mekras D, et al.
Prognostic markers in early-stage colorectal cancer: significance of TYMS mRNA expression.
Anticancer Res. 2014; 34(9):4949-62 [PubMed] Related Publications
BACKGROUND: Several studies have recently indicated the prognostic or predictive role of several biomarkers in colorectal cancer. We sought to investigate the prognostic value of prostaglandin synthase 2 (PTGS2), cyclooxygenase 2 (COX2), thymidylate synthetase (TYMS), thymidine phosphorylase (TYMP), dihydropyrimidine dehydrogenase (DPYD) and topoisomerase I (TOPO1) in colorectal cancer patients treated with 5-FU-based regimens, such as De Gramont and FOLFOX in the adjuvant setting.
MATERIALS AND METHODS: In total, 96 formalin-fixed paraffin-embedded and 30 fresh-frozen tumor tissue samples were evaluated using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and microarray gene expression profiling, respectively.
RESULTS: The majority of tumors exhibited protein overexpression of COX2 (69%), TYMS (75%) and TOPO1 (75%). There was a significant association of TYMP protein expression with T classification, gender and stage (p=0.040, p=0.041 and p=0.011, respectively). TOPO1 protein expression was correlated with TOPO1 mRNA expression and was positively associated with stage (p=0.002) and lymph node infiltration (p=0.004). In univariate analysis, patients with high TYMS mRNA expression were shown to have a significantly lower risk for progression and death (Wald's p=0.030 and p=0.015, respectively). However, in multivariate analysis, only a trend for decreased risk for death was shown in patients with high TYMS mRNA expression (Wald's p=0.083), while patients with high PTGS2 mRNA expression had a trend for lower risk for progression (p=0.064). Using supervised hierarchical clustering, based on the expression in fresh-frozen tumor tissue of PTGS2, TYMS, TYMP and DPYD, our 30 patients were separated into two clusters. One of the clusters was enriched with patients with infiltrated lymph nodes (p<0.05), suggesting that these genes might have an impact on the tumor's ability to metastasize.
CONCLUSION: These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.

Shaul YD, Freinkman E, Comb WC, et al.
Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition.
Cell. 2014; 158(5):1094-109 [PubMed] Free Access to Full Article Related Publications
It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the "mesenchymal metabolic signature" (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits.

Shigeta K, Ishii Y, Hasegawa H, et al.
Evaluation of 5-fluorouracil metabolic enzymes as predictors of response to adjuvant chemotherapy outcomes in patients with stage II/III colorectal cancer: a decision-curve analysis.
World J Surg. 2014; 38(12):3248-56 [PubMed] Related Publications
BACKGROUND: The effectiveness of 5-fluorouracil (5-FU)-based adjuvant chemotherapy is reported in patients with colorectal cancer (CRC), but the usefulness of 5-FU metabolic enzymes as predictive biomarkers of the efficacy of this chemotherapy remains unclear.
OBJECTIVE: This study aims to verify whether 5-FU metabolic enzymes are predictive biomarkers in the clinical setting of adjuvant chemotherapy for stage II/III CRC.
METHODS: In total, 179 patients with stage II/III CRC who were treated at our institute between 2000 and 2010 were enrolled. Messenger RNA (mRNA) expression of major 5-FU metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase (TP), orotate phosphoribosyl transferase, and β-actin (control) was evaluated using the Danenberg Tumor Profile method. mRNA expression and other clinicopathological data were investigated with regard to CRC relapse.
RESULTS: A total of 78 patients underwent surgery alone, while 101 underwent adjuvant chemotherapy (5-FU plus leucovorin [LV] or tegafur plus uracil /LV) following surgery. Relapse-free survival was longer and risk of recurrence was lower in association with high TP mRNA expression than in association with low TP mRNA expression in the adjuvant chemotherapy group (hazard ratio 0.66; 95 % confidence interval 0.47-0.92; p = 0.016), but not in the surgery alone group. mRNA expression of no other enzymes was associated with relapse in both groups. In decision-curve analyses, the predictive efficiency of TP mRNA expression plus clinicopathological factors was slightly better than that of clinicopathological factors only.
CONCLUSIONS: TP mRNA expression in tumors predicted the effects of adjuvant chemotherapy for stage II/III CRC, although the beneficial effects were marginal.

Kelemen LE, Terry KL, Goodman MT, et al.
Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.
Mol Nutr Food Res. 2014; 58(10):2023-35 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).
CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Elias D, Vever H, Lænkholm AV, et al.
Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy.
Oncogene. 2015; 34(15):1919-27 [PubMed] Related Publications
To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, whereas knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth- and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N=47) and the other with early disease (N=76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.

Cai X, Fang JM, Xue P, et al.
The role of IVS14+1 G > A genotype detection in the dihydropyrimidine dehydrogenase gene and pharmacokinetic monitoring of 5-fluorouracil in the individualized adjustment of 5-fluorouracil for patients with local advanced and metastatic colorectal cancer: a preliminary report.
Eur Rev Med Pharmacol Sci. 2014; 18(8):1247-58 [PubMed] Related Publications
AIM: We retrospectively investigated the relationship between IVS14+1 G > A genotype of the dihydropyrimidine dehydrogenase (DPD) gene with plasma concentration of 5-fluorouracil (5-FU) as well as adverse reactions in 80 patients with locally advanced or metastatic colorectal cancer.
PATIENTS AND METHODS: Eighty patients with un-resectable locally advanced or metastatic colorectal cancer were treated with Folfox-6 regimen, which repeated every two weeks for at least three cycles. Single nucleotide polymorphisms for DPD gene were analyzed before chemotherapy by high-resolution melting (HRM) analysis. The plasma concentration of fluorouracil was measured by high performance liquid chromatography (HPLC) after continuous infusion of fluorouracil over 12 h in each cycle. The average values of plasma concentrations in each cycle were calculated, and the factors related to plasma concentration of 5-FU were screened by stepwise regression.
RESULTS: All patients were divided into three groups according to the predictive confidence interval of plasma concentration of 5-FU, and the average plasma concentrations of fluorouracil in each cycle of these three groups were less than or equal to 26.83 mg/L, 26.83-40.62 mg/L, and more than 40.62 mg/L, respectively. Stepwise regression analysis showed that the plasma concentration of fluorouracil was associated with myelosuppression, hand-foot syndrome, diarrhea, overall survival (OS) and DPD genotype. In efficacy, the median progression-free survival PFS (mPFS) and OS (mOS) of group 2 and group 3 were both significantly higher than those of group 1.
CONCLUSIONS: Among the advanced colorectal cancer patients receiving fluorouracil-based chemotherapy, those with plasma concentration of 5-FU above 26.83 mg/L can obtain better survival; for patients with heterozygous DPD IVS14+1 mutation, 5-FU dose should be appropriately reduced according to last plasma concentration to reduce adverse reactions, while the homozygous ones should avoid application of 5-FU and its derivatives.

Mokrim M, Aftimos PG, Errihani H, Piccart-Gebhart M
Breast cancer, DPYD mutations and capecitabine-related ileitis: description of two cases and a review of the literature.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications
Despite many treatment advances, metastatic breast cancer remains an incurable disease and is the third leading cause of cancer-related deaths in Europe. Capecitabine has become a standard treatment option for metastatic breast cancer, as a single agent or in combination. Hand-foot syndrome and diarrhoea are the most frequently reported side effects, while capecitabine-related ileitis is very rare. Deficiency of dihydropyrimidine dehydrogenase activity leads to severe toxicities after administration of 5-fluorouracil or its prodrugs. We report two cases of patients with metastatic breast cancer who developed ileitis after treatment with capecitabine. One patient had a DPYD gene abnormality.

Suarez Martinez-Falero B, Gillmore R
A rare cause of susceptibility to neutropenic sepsis in a patient with metastatic pancreas cancer.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications
A 71-year-old patient receiving combination chemotherapy (irinotecan, oxaliplatin and 5-fluorouracil (5-FU)) for metastatic pancreas cancer was admitted after her first cycle of chemotherapy with a severe and unexpectedly prolonged episode of neutropenic sepsis associated with pancytopenia and marked mucositis. Owing to the unusual picture, the patient was tested for mutations in the gene encoding the enzyme dihydropyrimidine dehydrogenase (DPD)--an enzyme involved in the metabolism of the chemotherapy drug 5-FU. The patient was found to be heterozygous for a mutation, DPD IVS14+1G>A, leading to the severe toxicity exhibited following this regimen caused by delayed metabolism of 5-FU. She was treated aggressively with supportive care and recovered from this episode. Importantly she was subsequently switched to an alternative chemotherapy regimen to treat her disease. She continues to maintain an excellent quality of life some 9 months after her initial diagnosis on third-line chemotherapy.

Rosmarin D, Palles C, Pagnamenta A, et al.
A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.
Gut. 2015; 64(1):111-20 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
OBJECTIVE: Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS).
DESIGN: We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial.
RESULTS: We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10(-6)) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10(-5)). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10(-8)). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10(-6)). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5'VNTR 2R/3R and 3'UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression.
CONCLUSIONS: DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.

Hill MJ, Donocik JG, Nuamah RA, et al.
Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells.
Schizophr Res. 2014; 153(1-3):225-30 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
MIR137, transcribed as the microRNA miR-137, is one of the leading candidate schizophrenia susceptibility genes to arise from large genome-wide association studies (GWAS) of the disorder. Recent data suggest that miR-137 modulates the expression of other schizophrenia susceptibility genes. Although bioinformatic resources are available with which to predict genes regulated by individual microRNA, there has been a lack of empirical data on genome-wide gene expression changes following miR-137 manipulation. We have therefore performed a genome-wide assessment of transcriptional changes in a human neural progenitor cell line after miR-137 over-expression and inhibition in order to elucidate molecular pathways by which genetic perturbation of miR-137 could promote susceptibility to schizophrenia. Bioinformatically-predicted miR-137 targets showed a small but highly significant down-regulation following miR-137 over-expression. Genes that were significantly down-regulated in association with miR-137 over-expression were enriched for involvement in neuronal differentiation. Differentially expressed genes that were confirmed by qPCR included others at genome-wide significant risk loci for schizophrenia (MAD1L1 and DPYD) and BDNF. These data point to molecular pathways through which genetic variation at the MIR137 locus could confer risk for schizophrenia.

Huang MY, Wu CH, Huang CM, et al.
DPYD, TYMS, TYMP, TK1, and TK2 genetic expressions as response markers in locally advanced rectal cancer patients treated with fluoropyrimidine-based chemoradiotherapy.
Biomed Res Int. 2013; 2013:931028 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
This study is to investigate multiple chemotherapeutic agent- and radiation-related genetic biomarkers in locally advanced rectal cancer (LARC) patients following fluoropyrimidine-based concurrent chemoradiotherapy (CCRT) for response prediction. We initially selected 6 fluoropyrimidine metabolism-related genes (DPYD, ORPT, TYMS, TYMP, TK1, and TK2) and 3 radiotherapy response-related genes (GLUT1, HIF-1α, and HIF-2α) as targets for gene expression identification in 60 LARC cancer specimens. Subsequently, a high-sensitivity weighted enzymatic chip array was designed and constructed to predict responses following CCRT. After CCRT, 39 of 60 (65%) LARC patients were classified as responders (pathological tumor regression grade 2 ~ 4). Using a panel of multiple genetic biomarkers (chip), including DPYD, TYMS, TYMP, TK1, and TK2, at a cutoff value for 3 positive genes, a sensitivity of 89.7% and a specificity of 81% were obtained (AUC: 0.915; 95% CI: 0.840-0.991). Negative chip results were significantly correlated to poor CCRT responses (TRG 0-1) (P = 0.014, hazard ratio: 22.704, 95% CI: 3.055-235.448 in multivariate analysis). Disease-free survival analysis showed significantly better survival rate in patients with positive chip results (P = 0.0001). We suggest that a chip including DPYD, TYMS, TYMP, TK1, and TK2 genes is a potential tool to predict response in LARC following fluoropyrimidine-based CCRT.

Offer SM, Butterfield GL, Jerde CR, et al.
microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites.
Mol Cancer Ther. 2014; 13(3):742-51 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR-27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 μmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 μmol/L; P = 3.3 × 10(-5) and P = 1.5 × 10(-7), respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R(2) = 0.49; P = 0.0012) and miR-27b (R(2) = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity.

Saif MW, Lee AM, Offer SM, et al.
A DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxic effects: potential for an individualized medicine approach.
Mayo Clin Proc. 2014; 89(1):131-6 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.

Deng J, Lei W, Fu JC, et al.
Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro.
Biochem Biophys Res Commun. 2014; 443(3):789-95 [PubMed] Related Publications
5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

Kaira K, Yamamoto N, Endo M, et al.
¹⁸F-FDG uptake on PET is a predictive marker of thymidylate synthase expression in patients with thoracic neoplasms.
Oncol Rep. 2014; 31(1):209-15 [PubMed] Related Publications
The aim of this study was to investigate the relationship between the expression levels of thymidylate synthase (TS) and 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake on positron emission tomography (PET) in various thoracic neoplasms. In total, 392 patients [non-small cell lung cancer (NSCLC) (n=140), malignant pleural mesothelioma (MPM) (n=21), pulmonary metastatic tumors (PMT) (n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine (NE) tumor (n=34)] who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained using immunohistochemistry for determination of TS, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), vascular endothelial growth factor (VEGF), microvessel density (MVD), CD34 and p53. The expression of TS in thoracic neoplasms had a positivity of 58% (230/392), and the positive rates of TS expression in NSCLC, PMT, thymic epithelial tumor, NE tumor and MPM samples were 56, 57, 57, 85 and 47%, respectively. The positivity of TS expression was significantly higher in NE tumors compared to that in other thoracic tumors. A statistically significant correlation between TS expression and ¹⁸F-FDG uptake was observed in thoracic neoplasms, in particular primary lung adenocarcinomas, high-grade NE tumors, thymomas and MPMs. Moreover, TS expression was closely associated with angiogenesis, DPD, OPRT and p53. Our results indicated that SUV(max) by ¹⁸F-FDG uptake may be an alternative biomarker for predicting TS expression in patients with primary lung adenocarcinoma, high-grade NE tumor, thymoma and MPM.

Ide H, Kikuchi E, Hasegawa M, et al.
Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer.
Cancer Med. 2013; 2(4):488-95 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU-19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose-dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down-regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level.

Wei CH, Gorgan TR, Elashoff DA, et al.
A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers.
Pancreas. 2013; 42(8):1303-10 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
OBJECTIVES: The objective of this study was to summarize all clinical studies evaluating the prognostic role of gemcitabine (GEM) metabolic genes in pancreaticobiliary (PB) cancer patients receiving GEM therapy in the neoadjuvant, adjuvant, or palliative settings.
METHODS: Meta-analyses were performed to calculate the pooled hazard ratios for each gene by each clinical outcome (overall survival [OS], disease-free survival [DFS], and progression-free survival) using a random-effects approach.
RESULTS: The search strategy identified 16 eligible studies, composed of 632 PB patients total, with moderate quality. Compared with low expression, pooled hazard ratios for OS of hENT1, dCK, RRM1, RRM2, and DPD were 0.37 (95% confidence interval [CI], 0.28-0.47), 0.40 (95% CI, 0.20-0.80), 2.21 (95% CI, 1.12-4.36), 2.13 (95% CI, 1.00-4.52), and 1.91 (95% CI, 1.16-3.17), respectively. A similar trend was observed for each of these biomarkers in DFS and progression-free survival prognostication. Subgroup analyses for hENT1 showed a comparable survival correlation in the adjuvant and palliative settings.
CONCLUSIONS: High expression of hENT1 in PB cancer patients receiving GEM-based adjuvant therapy is associated with improved OS and DFS and may be the best examined prognostic marker to date. Evidence for other biomarkers is limited by a small number of publications investigating these markers.

Gross E, Meul C, Raab S, et al.
Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.
Br J Cancer. 2013; 109(9):2347-55 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment.
METHODS: DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues.
RESULTS: In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037).
CONCLUSION: Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.

Mekata E, Murata S, Sonoda H, et al.
Protein-bound polysaccharide-K augments the anticancer effect of fluoropyrimidine derivatives possibly by lowering dihydropyrimidine dehydrogenase expression in gastrointestinal cancers.
Oncol Rep. 2013; 30(6):2845-51 [PubMed] Related Publications
Protein-bound polysaccharide-K (PSK) enhances the antitumor effect of anticancer drug when used clinically in combination with such drugs. PSK is known to act by immune-mediated mechanisms; however, the relationship between PSK and metabolic enzymes of anticancer drugs is unknown. We used the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) clinically to evaluate the sensitivity of anticancer drugs. In the present study, we modified the CD-DST by adding peripheral blood mononuclear cells (PBMCs) (immuno-CD-DST) and examined the antitumor effect of PSK in combination with anticancer drugs. First, HCT116 human colon cancer cells were cultured with PSK and 5-fluorouracil (5-FU) or 5'-deoxy-5-fluorouridine (5'-DFUR) in the presence or absence of PBMCs, and the antiproliferative effects were compared. In the presence of PBMCs, PSK augmented the inhibitory effects of 5-FU and 5'-DFUR on HCT116 cell proliferation. Next, using human gastric cancer and colon cancer cell lines, the effects of PSK on mRNA expression of various metabolic enzymes of fluoropyrimidines: dihydropyrimidine dehydrogenase (DPD), thymidylate synthase, thymidine phosphorylase and orotate phosphoribosyl transferase, were examined by real-time PCR. PSK significantly enhanced DPD mRNA expression in all of the cancer cell lines tested, but not those of the other enzymes. Addition of IFN-α and TRAIL, cytokines known to inhibit DPD expression, to the cultures reduced DPD mRNA expression in the cancer cells. When PBMC samples collected from healthy volunteers were cultured with PSK, IFN-α mRNA expression increased in 3 of the 5 PBMC samples, while TRAIL mRNA expression was unchanged. The present results propose the possibility that PSK induces PBMCs to express IFN-α which inhibits DPD expression, and consequently augments the antitumor effect of 5-FU or 5'-DFUR. Immuno-CD-DST is useful for evaluating drugs with immunological mechanisms of action.

Alcazar-González GA, Calderón-Garcidueñas AL, Garza-Rodríguez ML, et al.
Comparative study of polymorphism frequencies of the CYP2D6, CYP3A5, CYP2C8 and IL-10 genes in Mexican and Spanish women with breast cancer.
Pharmacogenomics. 2013; 14(13):1583-92 [PubMed] Related Publications
AIM: Pharmacogenetic studies in breast cancer (BC) may predict the efficacy of tamoxifen and the toxicity of paclitaxel and capecitabine. We determined the frequency of polymorphisms in the CYP2D6 gene associated with activation of tamoxifen, and those of the genes CYP2C8, CYP3A5 and DPYD associated with toxicity of paclitaxel and capecitabine. We also included a IL-10 gene polymorphism associated with advanced tumor stage at diagnosis.
PATIENTS & METHODS: Genomic DNAs from 241 BC patients from northeast Mexico were genotyped using DNA microarray technology.
RESULTS: For tamoxifen processing, CYP2D6 genotyping predicted that 90.8% of patients were normal metabolizers, 4.2% ultrarapid, 2.1% intermediate and 2.9% poor metabolizers. For paclitaxel and the CYP2C8 gene, 75.3% were normal, 23.4% intermediate and 1.3% poor metabolizers. Regarding the DPYD gene, only one patient was a poor metabolizer. For the IL-10 gene, 47.1% were poor metabolizers.
CONCLUSION: These results contribute valuable information towards personalizing BC chemotherapy in Mexican women.

Teh LK, Hamzah S, Hashim H, et al.
Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients.
Ther Drug Monit. 2013; 35(5):624-30 [PubMed] Related Publications
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine.
METHODS: A total of 26 patients comprising 3 different ethnic groups (Malay, Chinese, and Indian) diagnosed with colorectal cancer and treated with 5-FU chemotherapy regimen from local hospital were recruited. Polymerase chain reaction and denaturing high-performance liquid chromatography methods were developed to screen polymorphisms of DPYD gene. High-performance liquid chromatography-based quantification assay was developed to measure the serum concentration of 5-FU among these patients.
RESULTS: Patients with DPYD genotypes of deficient enzyme activity had higher median serum levels of 5-FU compared with normal DPD group (median, 11.51 mcg/mL; 95% confidence interval, 10.18-16.11 versus median, 0.83 mcg/mL; 95% confidence interval, 0.55-5.90, Mann-Whitney U test; P = 0.010). Patients with neutropenia (n = 11) had significantly higher serum concentrations of 5-FU as compared with those with normal white blood cell count (n = 15) (Mann-Whitney U test, P = 0.031). Combined regression analysis showed that the predictive power of DPYD*5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T>C accounted for 29.9% of the occurrences of neutropenia (analysis of variance, P = 0.017).
CONCLUSIONS: This study revealed that DPYD*5 (rs1801159) and 1896 T>C (rs17376848) are potentially useful predictive markers of patients' responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia.

Terrazzino S, Cargnin S, Del Re M, et al.
DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis.
Pharmacogenomics. 2013; 14(11):1255-72 [PubMed] Related Publications
AIM: In the present study we conducted a systematic review and meta-analysis of published data to quantify the impact of the DPYD IVS14+1G>A and 2846A>T variants on the risk of fluoropyrimidine-related toxicities and to determine sensitivity and specificity testing for DPYD variants.
METHODS: Relevant studies were identified through PubMed and Web of Knowledge databases, studies included were those published up until to May 2012. Study quality was assessed according to the HuGENET guidelines and Strengthening the Reporting of Genetic Association (STREGA) recommendations.
RESULTS: Random-effects meta-analysis provided evidence that carriers of DPYD IVS14+1G>A are at higher risk of ≥3 degrees of overall grade toxicity, hematological toxicity, mucositis and diarrhea. In addition, a strong association was also found between carriers of the DPYD 2846T allele and overall grade ≥3 toxicity or grade ≥3 diarrhea. An inverse linear relationship was found in prospective studies between the odds ratio of DPYD IVS14+1G>A and the incidence of overall grade ≥3 toxicity, indicating an higher impact in cohorts in which the incidence of severe toxicity was lower.
CONCLUSION: The results of this meta-analysis confirm clinical validity of DPYD IVS14+1G>A and 2846A>T as risk factors for the development of severe toxicities following fluoropyrimidine treatment. Furthermore, the sensitivity and specificity estimates obtained could be useful in establishing the cost-effectiveness of testing for DPYD variants.

Yamada Y, Boku N, Nishina T, et al.
Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912.
Ann Oncol. 2013; 24(10):2560-5 [PubMed] Related Publications
BACKGROUND: Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer.
PATIENTS AND METHODS: Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point.
RESULTS: Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1.
CONCLUSION: These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer.
CLINICAL TRIAL NUMBER: C000000062, www.umin.ac.jp.

Takahashi M, Kawabata R, Kawano A, et al.
Substitution of anti-androgens and tegafur-uracil combination therapy for castration-resistant prostate cancer: results of a multi-center randomized phase II study.
Int J Oncol. 2013; 43(3):713-20 [PubMed] Related Publications
We conducted this study to determine whether substitution with anti-androgen (SOA) and tegafur-uracil (a pro‑drug of 5-FU) combination therapy is more effective than SOA alone after relapse from initial hormonal therapy. Patients who were histologically confirmed and relapsed after initial hormonal therapy were included. All patients were randomly allocated into two groups: SOA alone (group A) or SOA combined with tegafur-uracil (group B). The mRNA expression of four enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phospho-ribosyltransferase (OPRT) and thymidine phosphorylase (TP), in prostate cancer cells was analyzed by quantitative reverse-transcription polymerase chain reaction. Fifty-two patients were enrolled in this study. The median age was 77 (range: 47-92) years. The PSA response rate in group B (61.5%) tended to be higher compared to that in group A (34.6%) (p=0.095). Group B (median: 15.9 months) had a significantly longer time to PSA progression (TTP) compared to group A (6.4 months) (p=0.014). In patients with a lower TS expression or a higher OPRT expression, group B demonstrated a higher PSA response rate compared to group A (p=0.019 and p=0.041, respectively). In addition, in the patients with a lower TS expression, group B demonstrated a significantly longer TTP compared to group A (p=0.018). There were no severe adverse events in either treatment group. After relapse from initial hormonal therapy, SOA combined with tegafur-uracil is effective and well tolerated. The TS mRNA expression level may be a predictive factor for this combination therapy.

Saif MW, Garcon MC, Rodriguez G, Rodriguez T
Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series.
In Vivo. 2013 Jul-Aug; 27(4):531-4 [PubMed] Related Publications
BACKGROUND: 5-Fluorouracil (5-FU) is the backbone of chemotherapy regimens approved for treatment of colorectal cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far.
PATIENTS AND METHODS: We present a case series of six patients who developed cardiotoxicity on infusional fluorouracil and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies. Four patients were tested for polymorphic abnormality of the human dihydropyrimidine dehydrogenase gene (DPYD) with the TheraGuide 5-FU™ (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test.
RESULTS: Five patients were challenged with oral capecitabine that reproduced clinical and/or diagnostic concerns. All six patients tolerated bolus 5-FU either as a radiosensitizing agent or as chemotherapy without recurrence of a cardiac insult. DPYD was normal in the four patients tested.
CONCLUSION: Cardiotoxicity induced by 5-FU seems to be schedule-dependent. Bolus 5-FU can be used in patients developing cardiotoxicity due to 5-FU infusion or capecitabine with vigilance.

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