title: Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia.
abstract: Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.
authors.affiliation: Department of Pharmacy, USC School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Alachkar
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fulton
authors.affiliation: Alliance/CALGB Statistical Center, Duke Cancer Institute, Biostatistics, Durham, NC, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sanford
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Malnassy
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mutonga
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Stock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001215:Asparaginase / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult; D000099156:Superoxide Dismutase 2
chemical_list: D000970:Antineoplastic Agents; D001215:Asparaginase; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2