Pharmacogenomics of fluorouracil-based chemotherapy toxicity

Abstract

Introduction: 5-fluorouracil (5-FU), alone or in combination, is the most prevalent and effective chemotherapeutic agent for the treatment of cancers of the head and neck, breast, pancreas and gastrointestinal tract.

Areas covered: Three rare DPYD mutations, a splice mutation in intron 14 (c.1905+1G>A) and two nonsynonymous coding variants (c.1679T>G, c.2846A>T), have consistently been associated with severe 5-FU toxicity. A relatively common haplotype, hapB3, containing three intronic polymorphisms (c.483+18G>A; c.680+139G>A; c.959-51T>C) and a synonymous mutation c.1236G>A linked to c.1129-5923C>G, is a major contributor to early onset severe toxicity. TYMS VNTR 2R and TYMS-3′-UTR 6-bp ins-del variants were associated with global toxicity in capecitabine-treated patients. A candidate gene study of capecitabine-related toxicity reported that the s12132152 were strongly associated with hand-foot syndrome (HFS), whereas rs7548189 was associated with diarrhea. The rs2612091 and rs2741171, which are downstream of TYMS and intronic for ENOSF1, were associated with increased global toxicity and HFS.

Expert opinion: Sex-dependent differences, ethnicity, cancer types and 5-FU-based chemotherapy regimens might affect the heterogeneity of genetic variants for predictive 5-FU-related toxicity. Future approaches using genome-wide association analyses may help in identifying additional candidate genes causally involved in the path mechanisms of 5-FU-related toxicity.

Keywords:

• 5-fluorouracil
• dihydropyrimidine dehydrogenase
• methylene tetrahydrofolate reductase
• thymidylate synthase

Declaration of interest

The authors have received funding from the P30CA cancer care grant. However, the authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.

Notes