Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer

• Published in: British journal of cancer 2011-11, Vol.105 (11), p.1654-1662
• Main Authors: Thomas, F, Motsinger-Reif, A A, Hoskins, J M, Dvorak, A, Roy, S, Alyasiri, A, Myerson, R J, Fleshman, J W, Tan, B R, McLeod, H L
• Format: Article
• Language: English
• Subjects: 692/699/67/1504/1885/1777; 692/700/565/1436/434; Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer Research; Cancer therapies; Chemoradiotherapy, Adjuvant - adverse effects; Clinical Study; Colorectal cancer; Disease-Free Survival; Drug Resistance; Epidemiology; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; Humans; Irinotecan; Medical research; Medical sciences; Medicine; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Methylenetetrahydrofolate Reductase (NADPH2) - metabolism; Middle Aged; Molecular Medicine; Mucositis; Oncology; Pharmacogenetics - methods; Polymorphism, Genetic; Prospective Studies; Radiation therapy; Radiation-Sensitizing Agents - administration & dosage; Radiation-Sensitizing Agents - adverse effects; Rectal Neoplasms - enzymology; Rectal Neoplasms - genetics; Rectal Neoplasms - therapy; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Toxicity; Treatment Outcome; Tumors; Young Adult
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.442

Background: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. Methods: The germline DNA of 131 patients was genotyped for 10 variants in TYMS , MTHFR , DPYD , UGT1A1 , ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. Results: MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C–1298C) and diplotypes (CA–TA and TA–TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. Conclusion: MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.