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Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study
Authors: Caronia, D. (Daniela)
Patiño, A. (Ana)
Perez-Martinez, A. (Antonio)
Pita, G. (Guillermo)
Moreno, L.T. (Leticia Tais)
Zalacain, M. (Marta)
Molina, B. (Blanca)
Colmenero, I. (Isabel)
Sierrasesumaga, L. (Luis)
Benitez, J. (Javier)
Gonzalez-Neira, A. (Anna)
Keywords: Multidrug Resistance-Associated Proteins/genetics
Polymorphism, Single Nucleotide
Issue Date: 2011
Publisher: Public Library of Science
ISSN: 1932-6203
Citation: Caronia D, Patino-Garcia A, Perez-Martinez A, Pita G, Moreno LT, Zalacain-Diez M, et al. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study. PLoS One 2011;6(10):e26091.
Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response. METHODOLOGY/PRINCIPAL FINDINGS: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1x10(-)(5)), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9x10(-)(5)), rs1128503 and rs10276036 (r(2) = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9x10(-)(5)). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test]
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