title: Highlight on DPYD gene polymorphisms and treatment by capecitabine (.).
abstract: BACKGROUND
  Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine.
  
  
  METHODS
  A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 and 2.1% G4, including one toxic death. DPYD exome, flanking intronic regions (20 bp), 3'UTR and part of 5'UTR (500 bp) were sequenced on MiSeq Illumina (Integragen, 97% coverage, HWE checked).
  
  
  RESULTS
  In total, 48 SNPs were identified: three in 3'UTR, 19 in coding regions (four synonymous including E412E; 15 missenses including D949V, V732I, R592W, I560S, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 19 in flanking intronic regions (including *2A) and seven in 5'UTR. In total, 11 SNPs have not been previously described, including three missense variations each heterozygous in three separate patients: R696H, F100L and A26T. The patient with a toxic death carried one D949V allele. The three consensual variants *2A, D949V and I560S were carried by seven patients (heterozygous). Analysis of consensual variants showed that they were associated with G3-4 toxicity (OR = 21.0, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously associated with DPD deficiency in vitro, i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, OR = 21.1) and was predictive of G4 toxicity (sensitivity 40%, OR = 19.0). Of note, adding the new F100L variant further improved predictivity of genotyping on G4 toxicity (sensitivity 60%, OR = 42.8).
  
  
  CONCLUSIONS
  Present data establish the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity.
authors.affiliation: a Centre Antoine-Lacassagne , Nice Cedex , France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage* / Q000633:toxicity; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D018450:Disease Progression; D004334:Drug Administration Schedule; D005091:Exons; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017422:Sequence Analysis, DNA
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP)
keywords: Breast cancer; Dihydropyrimidine dehydrogenase; genotyping; mutations; toxicity