title: The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity.
abstract: A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; Pc.1637C>T*DPYD=0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Hamzic
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Wenger
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: T K
authors.initials: TK
authors.lastname: Froehlich
authors.affiliation: Department of Medical Oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Division of Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Aebi
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: C R
authors.initials: CR
authors.lastname: Largiadèr
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Amstutz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D055815:Young Adult
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D005472:Fluorouracil