title: Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients.
abstract: BACKGROUND
  Severe toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD).
  
  
  METHODS
  In this study, we evaluated DPYD promoter methylation through quantitative methylation-specific PCR and screened DPYD for large intragenic rearrangements in peripheral blood from 45 patients with gastrointestinal cancers who developed severe 5-FU toxicity. DPYD promoter methylation was also assessed in tumor tissue from 29 patients
  
  
  RESULTS
  Two cases with the IVS14+1G > A exon 14 skipping mutation (c.1905+1G > A), and one case carrying the 1845 G > T missense mutation (c.1845G > T) in the DPYD gene were identified. However, DPYD promoter methylation and large DPYD intragenic rearrangements were absent in all cases analyzed.
  
  
  CONCLUSIONS
  Our results indicate that DPYD promoter methylation and large intragenic rearrangements do not contribute significantly to the development of 5-FU severe toxicity in gastrointestinal cancer patients, supporting the need for additional studies on the mechanisms underlying genetic susceptibility to severe 5-FU toxicity.
authors.affiliation: Department of Medical Oncology, Portuguese Oncology Institute - Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Savva-Bordalo
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Vera L
authors.initials: VL
authors.lastname: Costa
authors.forename: Angelo
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Paula C
authors.initials: PC
authors.lastname: Dias
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Manuela
authors.initials: M
authors.lastname: Machado
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005770:Gastrointestinal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
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