TY - JOUR
T1 - Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane-based chemotherapy
T2 - A Gynecologic Oncology Group study
AU - Tian, Chunqiao
AU - Ambrosone, Christine B.
AU - Darcy, Kathleen M.
AU - Krivak, Thomas C.
AU - Armstrong, Deborah K.
AU - Bookman, Michael A.
AU - Davis, Warren
AU - Zhao, Hua
AU - Moysich, Kirsten
AU - Gallion, Holly
AU - Deloia, Julie A.
N1 - Funding Information:
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517) and to Roswell Park Cancer Institute (CA 016056–01) as well as grants from the Gynecologic Oncology Group/Ovarian Cancer Research Fund New Investigator Award (TK), The Jennie K. Scaife Foundation (JAD) and The Pittsburgh Foundation (JAD).
PY - 2012/3
Y1 - 2012/3
N2 - Purpose: Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy. Methods: Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model. Results: The C421A variant (CA + AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p = 0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.59-0.96, p = 0.022). The association between C421A and OS was not statistically significant (HR = 0.88, 95% CI = 0.67-1.15, p = 0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS. Conclusion: The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum + taxane-based chemotherapy. This finding requires further validation.
AB - Purpose: Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy. Methods: Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model. Results: The C421A variant (CA + AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p = 0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.59-0.96, p = 0.022). The association between C421A and OS was not statistically significant (HR = 0.88, 95% CI = 0.67-1.15, p = 0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS. Conclusion: The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum + taxane-based chemotherapy. This finding requires further validation.
KW - ABCB1
KW - ABCC2
KW - Advanced stage ovarian cancer
KW - Common variants
KW - GOG
UR - http://www.scopus.com/inward/record.url?scp=84856746185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856746185&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2011.11.022
DO - 10.1016/j.ygyno.2011.11.022
M3 - Article
C2 - 22112610
AN - SCOPUS:84856746185
SN - 0090-8258
VL - 124
SP - 575
EP - 581
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -