TY - JOUR
T1 - Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity
AU - McWhinney-Glass, Sarah
AU - Winham, Stacey J.
AU - Hertz, Daniel L.
AU - Revollo, Jane Yen
AU - Paul, Jim
AU - He, Yijing
AU - Brown, Robert
AU - Motsinger-Reif, Alison A.
AU - McLeod, Howard L.
PY - 2013/10/15
Y1 - 2013/10/15
N2 - Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapyinduced neurotoxicity. Patients and Methods: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1. Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival. Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.
AB - Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapyinduced neurotoxicity. Patients and Methods: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1. Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival. Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.
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U2 - 10.1158/1078-0432.CCR-13-0774
DO - 10.1158/1078-0432.CCR-13-0774
M3 - Article
C2 - 23963862
AN - SCOPUS:84886417617
SN - 1078-0432
VL - 19
SP - 5769
EP - 5776
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -