Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients.
OBJECTIVE
To evaluate the effect of thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) genotypes on toxicity in patients treated with capecitabine for advanced colorectal cancer and to determine the effect of these polymorphisms on the pretreatment levels of serum folate and plasma homocysteine.


METHODS
Fifty-four patients with a diagnosis of metastatic colorectal cancer were treated with fixed-dose capecitabine. Germ line DNA from patients was genotyped for TYMS TSER, TSER*3G>C, and 3'-untranslated 6 bp insertion/deletion (3' untranslated region insertion/deletion), and MTHFR c.677C>T and c.1298A>C using PCRs and RFLP. Toxicity was graded by National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed by Response Evaluation Criteria in Solid Tumors.


RESULTS
MTHFR c.677C>T and c.1298A>C genotypes and diplotypes predicted for grade 2/3 toxicities, whereas the TYMS genotypes had no influence. MTHFR c.677 genotype tended to predict overall survival (P = 0.08). MTHFR c.677 influenced pretreatment homocysteine (P < 0.05) and serum folate levels (P < 0.05). Multivariate analysis suggests that MTHFR c.1298 is an independent predictor of toxicity.


CONCLUSIONS
This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer. In addition, MTHFR single nucleotide polymorphisms predicted serum folate and plasma homocysteine levels, and, combined, these factors may be important predictors of capecitabine-induced toxicity.
Sharma
Rohini
R
Department of Molecular Pharmacology, Sydney Cancer Centre, University of Sydney, Sydney, New South Wales, Australia.
Hoskins
Janelle M
JM
Rivory
Laurent P
LP
Zucknick
Manuela
M
London
Rosyln
R
Liddle
Christopher
C
Clarke
Stephen J
SJ
D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D004742:Enhancer Elements, Genetic; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000633:toxicity; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013940:Thymidylate Synthase / Q000235:genetics*
D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000069287:Capecitabine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil