TY - JOUR
T1 - Impact of Polymorphic Variations of Gemcitabine Metabolism, DNA Damage Repair, and Drug-Resistance Genes on the Effect of High-Dose Chemotherapy for Relapsed or Refractory Lymphoid Malignancies
AU - Shinozuka, Keiji
AU - Tang, Hongwei
AU - Jones, Roy B.
AU - Li, Donghui
AU - Nieto, Yago
N1 - Publisher Copyright:
© 2016 American Society for Blood and Marrow Transplantation.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA, deoxycytidine kinase, and hCNT3; DNA damage repair genes RECQL, X-ray repair complementing 1, RAD54L, ATM, ATR, MLH1, MSH2, MSH3, TREX1, EXO1, and TP73; and multidrug-resistance genes MRP2 and MRP5; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS (P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity (P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed.
AB - The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA, deoxycytidine kinase, and hCNT3; DNA damage repair genes RECQL, X-ray repair complementing 1, RAD54L, ATM, ATR, MLH1, MSH2, MSH3, TREX1, EXO1, and TP73; and multidrug-resistance genes MRP2 and MRP5; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS (P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity (P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed.
KW - DNA damage repair
KW - Drug-resistance gene
KW - Gemcitabine metabolism
KW - Glutathione-S-transferases
KW - Single nucleotide polymorphisms
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U2 - 10.1016/j.bbmt.2015.12.022
DO - 10.1016/j.bbmt.2015.12.022
M3 - Article
C2 - 26743341
AN - SCOPUS:84960837067
SN - 1083-8791
VL - 22
SP - 843
EP - 849
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 5
ER -