University of Chicago Hospital, Chicago, IL
Navin R. Pinto , Mary J Emond , Charles Spiekerman , Arlene Naranjo , Karen W Makar , Julie R. Park , Jeannine S. McCune
Background: While outcomes for patients with high-risk neuroblastoma have improved over time, largely through intensification of therapy, biologic factors predictive of high-risk treatment failure remain elusive. Furthermore, the role of germline genetic variation in treatment failure has not been extensively investigated. Methods: Single nucleotide polymorphism (SNP) genotyping was performed on selected genes in the pharmacokinetic pathway of cyclophosphamide (CY) for children with high-risk neuroblastoma enrolled on the Children’s Oncology Group high-risk neuroblastoma protocol, ANBL0532. Response after two cycles of topotecan/CY (ranging from complete response to progressive disease) was used as a continuous outcome and with dominant model scoring of the SNP genotype as the independent variable for the association studies, adjusting for age at diagnosis, race (as determined by 30 genotyped SNPs serving as ancestry informative markers), stage, MYCN status and histology. Results: Of the 652 patients enrolled on ANBL0532, 303 participated in the pharmacogenetics aim. We tested 110 SNPs (in 37 genes) that were either tagging or had associations of interest previously reported. ABBC1 and ABCC4 had SNPs with nominal p-values < 0.01. After correction for multiple testing, two intronic SNPs in ABBC1, rs4148353 and rs17287570, were significantly associated with response to two cycles of topotecan/CY, p < 0.04 and p < 0.10, respectively. For both SNPs, the presence of one or more alternative alleles was associated with inferior outcome (coefficient estimate -0.56 and - 0.46, respectively). Conclusions: ABCC1, is a key regulator of chemotherapeutic cellular efflux, including CY. Genetic variants in ABCC1 which may alter the function of transporter impact outcome in children with high-risk neuroblastoma. Pediatric validation is underway in patients with rhabdomyosarcoma also treated with cyclophosphamide-containing regimens. Clinical trial information: NCT00567567
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