Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients

Savva-Bordalo, Joana; Ramalho-Carvalho, João; Pinheiro, Manuela; Costa, Vera L.; Rodrigues, Ângelo; Dias, Paula C.; Veiga, Isabel; Machado, Manuela; Teixeira, Manuel R.; Henrique, Rui; Jerónimo, Carmen

doi:10.1186/1471-2407-10-470

Cited by 18 publications

(11 citation statements)

References 25 publications

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“…64 In contrast, other studies did not confirm the role of DPYD promoter hypermethylation to the development of severe 5-FU toxicity. 66,67 The contradictory results of the studies investigating the role of methylation of the DPYD promoter make it unlikely that screening for aberrant methylation of the promoter of DPYD will become current practice soon.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

et al. 2013

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5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these tests.

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Section: Methodsmentioning

confidence: 99%

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

et al. 2013

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“…However, a number of studies have identified discrepancies between DPYD mRNA expression, DPD protein expression, and DPD enzymatic activity (for example (12, 13)), suggesting that DPD expression may be regulated at the post-transcriptional level. Promoter methylation has been proposed as a potential regulatory mechanism for DPD expression; (14, 15) however, more recent clinical studies failed to establish an association with toxicity (16). Recent data have suggested that microRNAs may post-transcriptionally regulate DPD expression in lung tumors, (17) although the contributions to 5-FU sensitivity and resistance have not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

microRNAs miR-27a and miR-27b Directly Regulate Liver Dihydropyrimidine Dehydrogenase Expression through Two Conserved Binding Sites

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Butterfield

Jerde

et al. 2014

Molecular Cancer Therapeutics

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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 anti-cancer 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 miR-27a and miR-27b. These microRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells over-expressing miR-27a or miR-27b was 4.4 μM (both), significantly lower than that for cells expressing a non-targeting (scramble) control microRNA (14.3 μM; 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 (R2=0.49, P=0.0012) and miR-27b (R2=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.

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“…DPYD overexpression in tumors acts as a significant target for cellular resistance to 5-FU (29). Deficiency of the enzyme dihydropyrimidine dehydrogenase, encoded by the DPYD gene, resulting from methylation of the DPYD promoter region, has been correlated with severe toxicity to 5-FU in patients with gastrointestinal cancer (30). Ezzeldin et al (17) demonstrated that methylation of the DPYD promoter region has a positive role in the down-regulation of DPD expression.…”

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confidence: 99%

Long noncoding RNA LINC00261 induces chemosensitization to 5‐fluorouracil by mediating methylation‐dependent repression of DPYD in human esophageal cancer

et al. 2018

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Approximately 85% of a single administered dose of 5-fluorouracil (5-FU) will be degraded by dihydropyrimidine dehydrogenase (DYPD). Studies have highlighted a link between the complete or partial loss of DYPD function and clinical responses to 5-FU; however, the underlying molecular basis of DPD deficiency remains poorly understood. Hence, the aim of the present study was to evaluate the prevailing hypothesis which suggests that overexpression of LINC00261 possesses the ability to modulate the methylation-dependent repression of DPYD, ultimately resulting in an elevation of the sensitivity of human esophageal cancer cells to 5-FU. LINC00261 levels were initially quantified, followed by analysis of DYPD methylation within the cancerous tissues collected from 75 patients diagnosed with esophageal cancer undergoing 5-FU-based adjuvant chemotherapy. In an attempt to determine the levels of LINC00261 related to the esophageal cancer cell resistance to 5-FU and to identify the interaction between the levels of LINC00261 and methylation of the DYPD promoter, esophageal cancer cells TE-1 and -5 were prepared, in which LINC00261 and the 5-FU-resistant TE-1 and -5 cells were overexpressed. The levels of LINC00261 were reduced among the cancerous tissues obtained from patients exhibiting resistance to 5-FU. Overexpression of LINC00261 was determined to dramatically inhibit proliferation and resistance to apoptosis among 5-FU-resistant TE-1 and -5 cells, whereas silencing of LINC00261 was determined to enhance proliferation and resistance to apoptosis among the TE-1 and -5 cells. DPYD, a confirmed target of LINC00261, displayed a greater incidence of DNA methylation among patient's sensitive to 5-FU. A key finding revealed that overexpressed LINC00261 could increase the methylation of the DPYD promoter through the recruitment of DNA methyltransferase (DNMT), which, in turn, acts to decrease DPYD activity in 5-FU-resistant TE-1 cells, whereas a reversible change was recorded once the demethylation reagent 5-aza-2'-deoxyctidine was employed to treat the 5-FU-resistant TE-1 cells. Taken together, the results of the study provided evidence emphasizing the distinct antitumor ability of LINC00261 in cases of esophageal cancer, which was manifested by overexpression of LINC00261 detected to increase the sensitivity of human esophageal cancer cells to 5-FU by mediating methylation-dependent repression of DPYD. Our study highlighted the potential of LINC00261 as a novel target capable of improving the chemotherapeutic response and survival of patients with esophageal cancer.-Lin, K., Jiang, H., Zhuang, S.-S., Qin, Y.-S., Qiu, G.-D., She, Y.-Q., Zheng, J.-T., Chen, C., Fang, L., Zhang, S.-Y. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

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Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients

Cited by 18 publications

References 25 publications

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

microRNAs miR-27a and miR-27b Directly Regulate Liver Dihydropyrimidine Dehydrogenase Expression through Two Conserved Binding Sites

Long noncoding RNA LINC00261 induces chemosensitization to 5‐fluorouracil by mediating methylation‐dependent repression of DPYD in human esophageal cancer

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