title: Frequent intragenic rearrangements of DPYD in colorectal tumours.
abstract: Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: A B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.affiliation: Centre Antoine Lacassagne, Laboratoire d'Oncopharmacologie, Nice cedex 2, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.affiliation: Unité de cancérologie digestive Hôpital Archet II, Nice cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Mahamat
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meijer
authors.affiliation: Hôpital Georges Pompidou, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: INSERM UMR_S910, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Olschwang
authors.affiliation: Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Gaub
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: R C M
authors.initials: RC
authors.lastname: Hennekam
authors.affiliation: Hôpital de L'Archet-CHU de Nice, Nice, France.
authors.forename: D
authors.initials: D
authors.lastname: Benchimol
authors.affiliation: Hôpital Tenon, Université Pierre et Marie Curie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Houry
authors.affiliation: Department of Surgery, University Hospital and Joseph Fourier University, Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Letoublon
authors.affiliation: Université Claude Bernard Lyon 1, Pierre bénite cedex, France.
authors.forename: F-N
authors.initials: FN
authors.lastname: Gilly
authors.affiliation: CHU Clermont Ferrand, Clermont Ferrand Cedex 1, France.
authors.forename: D
authors.initials: D
authors.lastname: Pezet
authors.affiliation: Department of medical Oncology, Saint Antoine Hospital, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Andre
authors.affiliation: Department of Surgery, University Hospital and Joseph Fourier University, Grenoble, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Faucheron
authors.affiliation: Department of Surgery, CHU de Nice, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Abderrahim-Ferkoune
authors.affiliation: MRC-Holland, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Vijzelaar
authors.affiliation: Centre Hospitalier Universitaire de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Pradere
authors.affiliation: Centre Antoine Lacassagne, Laboratoire d'Oncopharmacologie, Nice cedex 2, France.
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil