title: Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.
abstract: BACKGROUND
  The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity.
  
  
  METHODS
  We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction).
  
  
  RESULTS
  7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively).
  
  
  CONCLUSIONS
  DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Henricks
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Gabe S
authors.initials: GS
authors.lastname: Sonke
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Froehlich
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Jennings
authors.affiliation: Purine Research Laboratory, St Thomas' Hospital, London, UK.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.affiliation: Department of Gastroenterology, St Thomas' Hospital, London, UK.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Sanderson
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kleibl
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Kleiblova
authors.affiliation: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Molecular and Population Genetics Laboratory and Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Molecular and Population Genetics Laboratory and Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gross
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.affiliation: Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Koopman
authors.affiliation: Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. Electronic address: j.schellens@nki.nl.
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authors.initials: JH
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mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000069287:Capecitabine / Q000009:adverse effects / Q000493:pharmacokinetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006402:Hematologic Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D015999:Multivariate Analysis; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D005641:Tegafur / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D005641:Tegafur; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil