title: Impact of SHMT1 polymorphism on the clinical outcome of patients with metastatic colorectal cancer treated with first-line FOLFIRI+bevacizumab.
abstract: The impact of thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and serine hydroxymethyltransferase 1 (SHMT1) gene polymorphisms and that of dihydropyrimidine dehydrogenase (DPD) enzyme activity, serum total homocysteine level, and estimated serum creatinine clearance on first-line 5-fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI+bevacizumab) regimen efficacy in metastatic colorectal cancer patients was investigated. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed for TYMS 5'UTR variable number tandem repeat, TYMS 3'UTR ins/del, MTHFR C677T, and SHMT1 C1420T polymorphisms. The DPD activity of peripheral blood mononuclear cells was also determined. The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (P=0.034). Grade ≥2 hypertension was also an independent prognostic factor of longer progression-free survival and OS. Bevacizumab-related hypertension might be a predictive marker of treatment efficacy (P=0.0002 for OS) in the case of wild (CC) SHMT1 1420 genotypes only.
authors: National Institute of Oncology, Semmelweis University, Budapest, Hungary. budai@oncol.hu
authors: Barna
authors: B
authors: Budai
authors: Viktor
authors: V
authors: Komlósi
authors: Vilmos
authors: V
authors: Adleff
authors: Éva
authors: É
authors: Pap
authors: Andrea
authors: A
authors: Réti
authors: Tünde
authors: T
authors: Nagy
authors: Judit
authors: J
authors: Kralovánszky
authors: István
authors: I
authors: Láng
authors: Erika
authors: E
authors: Hitre
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000483:Alleles; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D003404:Creatinine / Q000097:blood; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000097:blood; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D056726:Genetic Association Studies; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D054643:INDEL Mutation; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D061067:Antibodies, Monoclonal, Humanized; D006710:Homocysteine; D000068258:Bevacizumab; D003404:Creatinine; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin