Microarray Reveals Concomitant Mutations Associated with 5-Fluorouracil Toxicity
DR LaFrance, M Lowery-Nordberg. Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA; Feist-Weiller Cancer Center, Shreveport, LA
Background: Approximately 30% of patients treated with 5-Fluorouracil (5FU) based chemotherapy develop significant toxic response. Toxicity has been associated with single nucleotide polymorphisms (SNPs) in dihydropyrimidine dehydrogenase (DPYD); thymidylate synthase (TYMS) and methyltetrahydrofolate reductase (MTHFR) have also been implicated. 5FU containing regimens are utilized frequently, however, due to its superior efficacy in the treatment of colon, breast, and head/neck carcinomas. The use of 5FU, along with the recent prioritization of personalized therapy, has highlighted the importance of pre-treatment evaluation of cancer patients for predicting chemotherapeutic response. We propose that the DNA microarray platform can identify SNPs associated with 5FU toxicity, and we predict that patients positive for SNPs will have an increased propensity toward developing toxicity when treated with 5FU.
Design: Using a multiplex microarray detection platform (Infiniti 5FU, AutoGenomics, Inc., Carlsbad, CA), DNA samples from 12 patients were analyzed for specific SNPs. The following were targeted: DPYD (85T>C, IVS14+1G>A, 1590T>C, 1679T>G, and 2846A>T), MTHFR (677C>T and 1298A>C), and TYMS (ins/del TTAAAG in the 3'-untranslated region). For patients with available follow-up information, the development of 5FU related toxicity was compared with mutation status.
Results: DNA microarray technology successfully identified SNPs in 13% of patients tested (4% homozygous, 9% heterozygous). Fifty eight percent of patients identified possessed SNPs in two of the target genes, with 33% having SNPs in DPYD and TYMS, MTHFR and DPYD affected in 17%, and 8% with MTHFR and TYMS SNPs. All 3 genes were affected in 17% of patients tested. Furthermore, 3 out of the 5 patients for which followup information was available demonstrated 5FU related toxicity requiring dose adjustment or treatment discontinuation. Two of the patients developing severe toxicity were positive for mutations in DPYD and TYMS; the third patient harbored mutations in all three target genes.
Conclusions: DNA microarray technology represents a novel method by which SNPs associated with 5FU toxicity can be detected. Our data supports the position that such mutations may indeed predispose patients to 5FU induced side effects. Additionally, the potential of concomitant mutations to further exacerbate 5FU induced chemotoxicity is intriguing and presents an opportunity for additional research.
Monday, March 22, 2010 1:00 PM
Poster Session II # 246, Monday Afternoon