ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

Ellen L Hedditch; Bo Gao; Amanda J Russell; Yi Lu; Catherine Emmanuel; Jonathan Beesley; Sharon E Johnatty; Xiaoqing Chen; Paul Harnett; Joshy George; Rebekka T Williams; Claudia Flemming; Diether Lambrechts; Evelyn Despierre; Sandrina Lambrechts; Ignace Vergote; Beth Karlan; Jenny Lester; Sandra Orsulic; Christine Walsh; Peter Fasching; Matthias W Beckmann; Arif B Ekici; Alexander Hein; Keitaro Matsuo; Satoyo Hosono; Toru Nakanishi; Yasushi Yatabe; Tanja Pejovic; Yukie Bean; Florian Heitz; Philipp Harter; Andreas du Bois; Ira Schwaab; Estrid Hogdall; Susan K Kjaer; Allan Jensen; Claus Hogdall; Lene Lundvall; Svend Aage Engelholm; Bob Brown; James Flanagan; Michelle D Metcalf; Nadeem Siddiqui; Thomas Sellers; Brooke Fridley; Julie Cunningham; Joellen Schildkraut; Ed Iversen; Rachel P Weber; Australian Ovarian Cancer Study Group

doi:10.1093/jnci/dju149

ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

Ellen L Hedditch, Bo Gao, Amanda J Russell, Yi Lu, Catherine Emmanuel, Jonathan Beesley, Sharon E Johnatty, Xiaoqing Chen, Paul Harnett, Joshy George, Rebekka T Williams, Claudia Flemming, Diether Lambrechts, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Beth Karlan, Jenny Lester, Sandra Orsulic, Christine WalshPeter Fasching, Matthias W Beckmann, Arif B Ekici, Alexander Hein, Keitaro Matsuo, Satoyo Hosono, Toru Nakanishi, Yasushi Yatabe, Tanja Pejovic, Yukie Bean, Florian Heitz, Philipp Harter, Andreas du Bois, Ira Schwaab, Estrid Hogdall, Susan K Kjaer, Allan Jensen, Claus Hogdall, Lene Lundvall, Svend Aage Engelholm, Bob Brown, James Flanagan, Michelle D Metcalf, Nadeem Siddiqui, Thomas Sellers, Brooke Fridley, Julie Cunningham, Joellen Schildkraut, Ed Iversen, Rachel P Weber, Australian Ovarian Cancer Study Group

Institut for Klinisk Medicin

77 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	dju149
Tidsskrift	National Cancer Institute. Journal (Print)
Vol/bind	106
Udgave nummer	7
Sider (fra-til)	1-11
Antal sider	11
ISSN	0027-8874
DOI	https://doi.org/10.1093/jnci/dju149
Status	Udgivet - 9 jul. 2014

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Hedditch, E. L., Gao, B., Russell, A. J., Lu, Y., Emmanuel, C., Beesley, J., Johnatty, S. E., Chen, X., Harnett, P., George, J., Williams, R. T., Flemming, C., Lambrechts, D., Despierre, E., Lambrechts, S., Vergote, I., Karlan, B., Lester, J., Orsulic, S., ... Australian Ovarian Cancer Study Group (2014). ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer. National Cancer Institute. Journal (Print), 106(7), 1-11. [dju149]. https://doi.org/10.1093/jnci/dju149

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, MW, 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 & Australian Ovarian Cancer Study Group 2014, 'ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer', National Cancer Institute. Journal (Print), bind 106, nr. 7, dju149, s. 1-11. https://doi.org/10.1093/jnci/dju149

@article{6fcfde95e4754c64844928ab4e58c767,

title = "ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer",

abstract = "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.",

keywords = "ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Cell Movement, Cystadenocarcinoma, Serous, Female, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Humans, Kaplan-Meier Estimate, Neoplasm Grading, Neoplasms, Glandular and Epithelial, Neoplastic Stem Cells, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction",

author = "Hedditch, {Ellen L} and Bo Gao and Russell, {Amanda J} and Yi Lu and Catherine Emmanuel and Jonathan Beesley and Johnatty, {Sharon E} and Xiaoqing Chen and Paul Harnett and Joshy George and Williams, {Rebekka T} and Claudia Flemming and Diether Lambrechts and Evelyn Despierre and Sandrina Lambrechts and Ignace Vergote and Beth Karlan and Jenny Lester and Sandra Orsulic and Christine Walsh and Peter Fasching and Beckmann, {Matthias W} and Ekici, {Arif B} and Alexander Hein and Keitaro Matsuo and Satoyo Hosono and Toru Nakanishi and Yasushi Yatabe and Tanja Pejovic and Yukie Bean and Florian Heitz and Philipp Harter and {du Bois}, Andreas and Ira Schwaab and Estrid Hogdall and Kjaer, {Susan K} and Allan Jensen and Claus Hogdall and Lene Lundvall and Engelholm, {Svend Aage} and Bob Brown and James Flanagan and Metcalf, {Michelle D} and Nadeem Siddiqui and Thomas Sellers and Brooke Fridley and Julie Cunningham and Joellen Schildkraut and Ed Iversen and Weber, {Rachel P} and {Australian Ovarian Cancer Study Group}",

year = "2014",

month = jul,

day = "9",

doi = "10.1093/jnci/dju149",

language = "English",

volume = "106",

pages = "1--11",

journal = "National Cancer Institute. Journal (Print)",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "7",

}

TY - JOUR

T1 - ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

AU - Hedditch, Ellen L

AU - Gao, Bo

AU - Russell, Amanda J

AU - Lu, Yi

AU - Emmanuel, Catherine

AU - Beesley, Jonathan

AU - Johnatty, Sharon E

AU - Chen, Xiaoqing

AU - Harnett, Paul

AU - George, Joshy

AU - Williams, Rebekka T

AU - Flemming, Claudia

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Karlan, Beth

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Walsh, Christine

AU - Fasching, Peter

AU - Beckmann, Matthias W

AU - Ekici, Arif B

AU - Hein, Alexander

AU - Matsuo, Keitaro

AU - Hosono, Satoyo

AU - Nakanishi, Toru

AU - Yatabe, Yasushi

AU - Pejovic, Tanja

AU - Bean, Yukie

AU - Heitz, Florian

AU - Harter, Philipp

AU - du Bois, Andreas

AU - Schwaab, Ira

AU - Hogdall, Estrid

AU - Kjaer, Susan K

AU - Jensen, Allan

AU - Hogdall, Claus

AU - Lundvall, Lene

AU - Engelholm, Svend Aage

AU - Brown, Bob

AU - Flanagan, James

AU - Metcalf, Michelle D

AU - Siddiqui, Nadeem

AU - Sellers, Thomas

AU - Fridley, Brooke

AU - Cunningham, Julie

AU - Schildkraut, Joellen

AU - Iversen, Ed

AU - Weber, Rachel P

AU - Australian Ovarian Cancer Study Group

PY - 2014/7/9

Y1 - 2014/7/9

N2 - 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.

AB - 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.

KW - ATP Binding Cassette Transporter 1

KW - ATP-Binding Cassette Transporters

KW - Cell Movement

KW - Cystadenocarcinoma, Serous

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genome-Wide Association Study

KW - Humans

KW - Kaplan-Meier Estimate

KW - Neoplasm Grading

KW - Neoplasms, Glandular and Epithelial

KW - Neoplastic Stem Cells

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

U2 - 10.1093/jnci/dju149

DO - 10.1093/jnci/dju149

M3 - Journal article

C2 - 24957074

SN - 0027-8874

VL - 106

SP - 1

EP - 11

JO - National Cancer Institute. Journal (Print)

JF - National Cancer Institute. Journal (Print)

IS - 7

M1 - dju149

ER -

ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

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