ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

被引：99

作者：

Hedditch, Ellen L. ^{[1
]}

Gao, Bo ^{[2
,3
]}

Russell, Amanda J. ^{[1
]}

Lu, Yi ^{[5
]}

Emmanuel, Catherine ^{[2
,3
]}

Beesley, Jonathan ^{[5
]}

Johnatty, Sharon E. ^{[5
]}

Chen, Xiaoqing ^{[5
]}

Harnett, Paul ^{[3
,4
]}

George, Joshy ^{[6
]}

Williams, Rebekka T. ^{[1
]}

Flemming, Claudia ^{[1
]}

Lambrechts, Diether ^{[7
]}

Despierre, Evelyn ^{[8
,9
]}

Lambrechts, Sandrina ^{[8
,9
]}

Vergote, Ignace ^{[8
,9
]}

Karlan, Beth ^{[10
]}

Lester, Jenny ^{[10
]}

Orsulic, Sandra ^{[10
]}

Walsh, Christine ^{[10
]}

Fasching, Peter ^{[11
,12
]}

Beckmann, Matthias W. ^{[11
]}

Ekici, Arif B. ^{[13
]}

Hein, Alexander ^{[11
]}

Matsuo, Keitaro ^{[13
]}

Hosono, Satoyo ^{[13
]}

Nakanishi, Toru ^{[14
]}

Yatabe, Yasushi ^{[15
]}

Pejovic, Tanja ^{[16
,17
]}

Bean, Yukie ^{[16
,17
]}

Heitz, Florian ^{[18
,19
,20
]}

Harter, Philipp ^{[21
]}

du Bois, Andreas ^{[21
]}

Schwaab, Ira ^{[21
]}

Hogdall, Estrid ^{[22
,23
]}

Kjaer, Susan K. ^{[22
,24
]}

Jensen, Allan ^{[22
]}

Hogdall, Claus ^{[25
]}

Lundvall, Lene ^{[25
]}

Engelholm, Svend Aage ^{[26
]}

Brown, Bob ^{[27
]}

Flanagan, James ^{[27
]}

Metcalf, Michelle D. ^{[27
]}

Siddiqui, Nadeem ^{[28
]}

Sellers, Thomas ^{[29
]}

Fridley, Brooke ^{[30
]}

Cunningham, Julie ^{[31
]}

Schildkraut, Joellen ^{[32
,34
]}

Iversen, Ed ^{[35
]}

Weber, Rachel P. ^{[32
]}

机构：

[1] Childrens Canc Inst Australia, Randwick, NSW, Australia

[2] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Dept Gynaecol Oncol, Sydney, NSW 2006, Australia

[3] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW 2006, Australia

[4] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Crown Princess Mary Canc Ctr, Sydney, NSW 2006, Australia

[5] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[6] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[7] VIB, Vesalius Res Ctr, Leuven, Belgium

[8] Univ Leuven, Dept Oncol, Leuven, Belgium

[9] Univ Hosp Leuven, Leuven, Belgium

[10] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA

[11] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen Nuremberg, Erlangen, Germany

[12] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA

[13] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan

[14] Aichi Canc Ctr, Cent Hosp, Dept Gynecol, Nagoya, Aichi 464, Japan

[15] Aichi Canc Ctr, Cent Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 464, Japan

[16] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA

[17] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[18] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen Nuremberg, Inst Human Genet, Erlangen, Germany

[19] Huyssens Stiftung Knappschaft GmbH, Kliniken Essen Mitte Evang, Dept Gynecol & Gynecol Oncol, Essen, Germany

[20] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany

[21] Inst Human Genet & Anthropol, Wiesbaden, Germany

[22] Danish Canc Soc Res Ctr, Unit Virus Lifestyle & Genes, Copenhagen, Denmark

[23] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark

[24] Univ Copenhagen, Rigshosp, Dept Obstet & Gynecol, DK-2100 Copenhagen, Denmark

[25] Univ Copenhagen, Rigshosp, Gynecol Clin, DK-2100 Copenhagen, Denmark

[26] Univ Copenhagen, Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark

[27] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England

[28] North Glasgow Univ Hosp NHS Trust, Stobhill Hospitall, Glasgow, Lanark, Scotland

[29] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[30] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA

[31] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[32] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA

[33] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA

[34] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA

[35] Duke Univ, Dept Stat Sci, Durham, NC USA

来源：

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2014年 / 106卷 / 07期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

SPHINGOSINE; 1-PHOSPHATE; CELLULAR CHOLESTEROL; THERAPEUTIC TARGET; MIGRATION; ASSOCIATION; METASTASIS; INVASION; MEDIATOR; ROLES;

D O I：

10.1093/jnci/dju149

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background 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. Methods 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. Results 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. Conclusions Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

引用

页数：11

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