title: 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.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.
authors.forename: M Wasif
authors.initials: MW
authors.lastname: Saif
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Offer
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McConnell
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Relias
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D001741:Black or African American / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000187:drug effects / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005819:Genetic Markers; D006360:Heat-Shock Proteins; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D010446:Peptide Fragments; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D005819:Genetic Markers; D006360:Heat-Shock Proteins; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; C063820:SNP nonapeptide; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil
keywords: 5-FU; 5-fluorouracil; 5-fluorouracil, leucovorin, oxaliplatin; DPD; FOLFOX; INR; PCR; base pair; bp; dihydropyrimidine dehydrogenase; international normalized ratio; polymerase chain reaction