Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment.
OBJECTIVE
The importance of polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD.


METHODS
The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed.


RESULTS
None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic polymorphisms (IVS5+18G>A, IVS6+139G>A and IVS9-51T>G) and a synonymous mutation (c.1236G>A), which was observed five- out of eight-times in patients with severe adverse effects.


CONCLUSIONS
The association of a haplotype containing no nonsynonymous or splice-site polymorphisms indicates that additional important genetic variation may be located in noncoding gene regions. Furthermore, a comparison with other studies suggests that the relative importance of particular DPYD mutations (IVS14+1G>A and c.2846A>T) for predicting severe 5-FU toxicity differs geographically across Europe.
Amstutz
Ursula
U
Institute of Clinical Chemistry, Inselspital, Bern University Hospital & University of Bern, INO F, CH-3010 Bern, Switzerland.
Farese
Simone
S
Aebi
Stefan
S
Largiadèr
Carlo R
CR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity*; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil