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

A Gynecologic Oncology Group study

Chunqiao Tian, Christine B. Ambrosone, Kathleen M. Darcy, Thomas C. Krivak, Deborah Kay Armstrong, Michael A. Bookman, Warren Davis, Hua Zhao, Kirsten Moysich, Holly Gallion, Julie A. Deloia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)575-581
Number of pages7
JournalGynecologic Oncology
Volume124
Issue number3
DOIs
StatePublished - Mar 2012

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Platinum
Ovarian Neoplasms
Disease-Free Survival
Drug Therapy
Genes
Survival
Genotype
Confidence Intervals
ATP-Binding Cassette Transporters
Patents
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Genetic Polymorphisms
Proportional Hazards Models
Proteolysis
Disease Progression
Neoplasms
Multivariate Analysis
taxane
DNA
Pharmaceutical Preparations

Keywords

  • ABCB1
  • ABCC2
  • Advanced stage ovarian cancer
  • Common variants
  • GOG

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

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 : A Gynecologic Oncology Group study. / Tian, Chunqiao; Ambrosone, Christine B.; Darcy, Kathleen M.; Krivak, Thomas C.; Armstrong, Deborah Kay; Bookman, Michael A.; Davis, Warren; Zhao, Hua; Moysich, Kirsten; Gallion, Holly; Deloia, Julie A.

In: Gynecologic Oncology, Vol. 124, No. 3, 03.2012, p. 575-581.

Research output: Contribution to journalArticle

Tian, Chunqiao ; Ambrosone, Christine B. ; Darcy, Kathleen M. ; Krivak, Thomas C. ; Armstrong, Deborah Kay ; Bookman, Michael A. ; Davis, Warren ; Zhao, Hua ; Moysich, Kirsten ; Gallion, Holly ; Deloia, Julie A. / 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 : A Gynecologic Oncology Group study. In: Gynecologic Oncology. 2012 ; Vol. 124, No. 3. pp. 575-581.
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abstract = "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.",
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T2 - A Gynecologic Oncology Group study

AU - Tian, Chunqiao

AU - Ambrosone, Christine B.

AU - Darcy, Kathleen M.

AU - Krivak, Thomas C.

AU - Armstrong, Deborah Kay

AU - Bookman, Michael A.

AU - Davis, Warren

AU - Zhao, Hua

AU - Moysich, Kirsten

AU - Gallion, Holly

AU - Deloia, Julie A.

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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.

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