ABCA transporter gene expression and poor outcome in epithelial ovarian cancer

Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, Johnatty SE, Chen X, Harnett P, George J, Williams RT, Flemming C, Lambrechts D, Despierre E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching P, Beckmann M, Ekici AB, Hein A, Matsuo K, Hosono S, Nakanishi T, Yatabe Y, Pejovic T, Bean Y, Heitz F, Harter P, Du Bois A, Schwaab I, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Lundvall L, Engelholm SA, Brown B, Flanagan J, Metcalf MD, Siddiqui N, Sellers T, Fridley B, Cunningham J, Schildkraut J, Iversen E, Weber RP, Berchuck A, Goode E, Bowtell DD, Chenevix-Trench G, Defazio A, Norris MD, Macgregor S, Haber M, Henderson MJ (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 106

Journal Issue: 7

DOI: 10.1093/jnci/dju149

Abstract

ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided.Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Authors with CRIS profile

Involved external institutions

Cedars-Sinai Medical Center United States (USA) (US) Institut für Humangenetik Wiesbaden Germany (DE) University of Copenhagen Denmark (DK) Oregon Health and Science University (OSHU) United States (USA) (US) Children's Cancer Institute Australia Australia (AU) University of Sydney (USYD) Australia (AU) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Peter MacCallum Cancer Centre Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Aichi Cancer Center Research Institute Japan (JP) Danish Cancer Society Research Center Denmark (DK) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) NHS Greater Glasgow and Clyde United Kingdom (GB) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Mayo Clinic United States (USA) (US) Duke University United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE)

How to cite

APA:

Hedditch, E.L., Gao, B., Russell, A.J., Lu, Y., Emmanuel, C., Beesley, J.,... Henderson, M.J. (2014). ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. Journal of the National Cancer Institute, 106(7). https://doi.org/10.1093/jnci/dju149

MLA:

Hedditch, Ellen L., et al. "ABCA transporter gene expression and poor outcome in epithelial ovarian cancer." Journal of the National Cancer Institute 106.7 (2014).

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