ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Sharon E Johnatty; Jonathan Beesley; Bo Gao; Xiaoqing Chen; Yi Lu; Matthew H Law; Michelle J Henderson; Amanda J Russell; Ellen L Hedditch; Catherine Emmanuel; Sian Fereday; Penelope M Webb; Ellen L Goode; Robert A Vierkant; Brooke L Fridley; Julie M Cunningham; Peter A Fasching; Matthias W Beckmann; Arif B Ekici; Estrid Hogdall; Susanne K Kjaer; Allan Jensen; Claus Hogdall; Robert James (Jim) Brown; Jim Paul; Sandrina Lambrechts; Evelyn Despierre; Ignace Vergote; Jenny Lester; Beth Y Karlan; Florian Heitz; Andreas du Bois; Philipp Harter; Ira Schwaab; Yukie Bean; Tanja Pejovic; Douglas A Levine; Marc T Goodman; Michael E Camey; Pamela J Thompson; Galina Lurie; Joellen Shildkraut; Andrew Berchuck; Kathryn L Terry; Daniel W Cramer; Murray D Norris; Michelle Haber; Stuart MacGregor; Anna deFazio; Georgia Chenevix-Trench; Australian Ovarian Cancer Study Group

doi:10.1016/j.ygyno.2013.07.107

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Sharon E Johnatty, Jonathan Beesley, Bo Gao, Xiaoqing Chen, Yi Lu, Matthew H Law, Michelle J Henderson, Amanda J Russell, Ellen L Hedditch, Catherine Emmanuel, Sian Fereday, Penelope M Webb, Ellen L Goode, Robert A Vierkant, Brooke L Fridley, Julie M Cunningham, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Estrid HogdallSusanne K Kjaer, Allan Jensen, Claus Hogdall, Robert James (Jim) Brown, Jim Paul, Sandrina Lambrechts, Evelyn Despierre, Ignace Vergote, Jenny Lester, Beth Y Karlan, Florian Heitz, Andreas du Bois, Philipp Harter, Ira Schwaab, Yukie Bean, Tanja Pejovic, Douglas A Levine, Marc T Goodman, Michael E Camey, Pamela J Thompson, Galina Lurie, Joellen Shildkraut, Andrew Berchuck, Kathryn L Terry, Daniel W Cramer, Murray D Norris, Michelle Haber, Stuart MacGregor, Anna deFazio, Georgia Chenevix-Trench, Australian Ovarian Cancer Study Group

Department of Clinical Medicine

43 Citations (Scopus)

Abstract

Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

Original language	English
Journal	Gynecologic Oncology
Volume	131
Issue number	1
Pages (from-to)	8-14
Number of pages	7
ISSN	0090-8258
DOIs	https://doi.org/10.1016/j.ygyno.2013.07.107
Publication status	Published - Oct 2013

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Johnatty, S. E., Beesley, J., Gao, B., Chen, X., Lu, Y., Law, M. H., Henderson, M. J., Russell, A. J., Hedditch, E. L., Emmanuel, C., Fereday, S., Webb, P. M., Goode, E. L., Vierkant, R. A., Fridley, B. L., Cunningham, J. M., Fasching, P. A., Beckmann, M. W., Ekici, A. B., ... Group, A. O. C. S. (2013). ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Gynecologic Oncology, 131(1), 8-14. https://doi.org/10.1016/j.ygyno.2013.07.107

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. / Johnatty, Sharon E; Beesley, Jonathan; Gao, Bo et al.
In: Gynecologic Oncology, Vol. 131, No. 1, 10.2013, p. 8-14.

Research output: Contribution to journal › Journal article › Research › peer-review

Johnatty, SE, Beesley, J, Gao, B, Chen, X, Lu, Y, Law, MH, Henderson, MJ, Russell, AJ, Hedditch, EL, Emmanuel, C, Fereday, S, Webb, PM, Goode, EL, Vierkant, RA, Fridley, BL, Cunningham, JM, Fasching, PA, Beckmann, MW, Ekici, AB, Hogdall, E , Kjaer, SK, Jensen, A, Hogdall, C, Brown, RJ, Paul, J, Lambrechts, S, Despierre, E, Vergote, I, Lester, J, Karlan, BY, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Bean, Y, Pejovic, T, Levine, DA, Goodman, MT, Camey, ME, Thompson, PJ, Lurie, G, Shildkraut, J, Berchuck, A, Terry, KL, Cramer, DW, Norris, MD, Haber, M, MacGregor, S, deFazio, A, Chenevix-Trench, G & Group, AOCS 2013, 'ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas', Gynecologic Oncology, vol. 131, no. 1, pp. 8-14. https://doi.org/10.1016/j.ygyno.2013.07.107

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title = "ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas",

abstract = "Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.",

author = "Johnatty, {Sharon E} and Jonathan Beesley and Bo Gao and Xiaoqing Chen and Yi Lu and Law, {Matthew H} and Henderson, {Michelle J} and Russell, {Amanda J} and Hedditch, {Ellen L} and Catherine Emmanuel and Sian Fereday and Webb, {Penelope M} and Goode, {Ellen L} and Vierkant, {Robert A} and Fridley, {Brooke L} and Cunningham, {Julie M} and Fasching, {Peter A} and Beckmann, {Matthias W} and Ekici, {Arif B} and Estrid Hogdall and Kjaer, {Susanne K} and Allan Jensen and Claus Hogdall and Brown, {Robert James (Jim)} and Jim Paul and Sandrina Lambrechts and Evelyn Despierre and Ignace Vergote and Jenny Lester and Karlan, {Beth Y} and Florian Heitz and {du Bois}, Andreas and Philipp Harter and Ira Schwaab and Yukie Bean and Tanja Pejovic and Levine, {Douglas A} and Goodman, {Marc T} and Camey, {Michael E} and Thompson, {Pamela J} and Galina Lurie and Joellen Shildkraut and Andrew Berchuck and Terry, {Kathryn L} and Cramer, {Daniel W} and Norris, {Murray D} and Michelle Haber and Stuart MacGregor and Anna deFazio and Georgia Chenevix-Trench and Group, {Australian Ovarian Cancer Study}",

year = "2013",

month = oct,

doi = "10.1016/j.ygyno.2013.07.107",

language = "English",

volume = "131",

pages = "8--14",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press",

number = "1",

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TY - JOUR

T1 - ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival

T2 - A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

AU - Johnatty, Sharon E

AU - Beesley, Jonathan

AU - Gao, Bo

AU - Chen, Xiaoqing

AU - Lu, Yi

AU - Law, Matthew H

AU - Henderson, Michelle J

AU - Russell, Amanda J

AU - Hedditch, Ellen L

AU - Emmanuel, Catherine

AU - Fereday, Sian

AU - Webb, Penelope M

AU - Goode, Ellen L

AU - Vierkant, Robert A

AU - Fridley, Brooke L

AU - Cunningham, Julie M

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Ekici, Arif B

AU - Hogdall, Estrid

AU - Kjaer, Susanne K

AU - Jensen, Allan

AU - Hogdall, Claus

AU - Brown, Robert James (Jim)

AU - Paul, Jim

AU - Lambrechts, Sandrina

AU - Despierre, Evelyn

AU - Vergote, Ignace

AU - Lester, Jenny

AU - Karlan, Beth Y

AU - Heitz, Florian

AU - du Bois, Andreas

AU - Harter, Philipp

AU - Schwaab, Ira

AU - Bean, Yukie

AU - Pejovic, Tanja

AU - Levine, Douglas A

AU - Goodman, Marc T

AU - Camey, Michael E

AU - Thompson, Pamela J

AU - Lurie, Galina

AU - Shildkraut, Joellen

AU - Berchuck, Andrew

AU - Terry, Kathryn L

AU - Cramer, Daniel W

AU - Norris, Murray D

AU - Haber, Michelle

AU - MacGregor, Stuart

AU - deFazio, Anna

AU - Chenevix-Trench, Georgia

AU - Group, Australian Ovarian Cancer Study

PY - 2013/10

Y1 - 2013/10

N2 - Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

AB - Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

U2 - 10.1016/j.ygyno.2013.07.107

DO - 10.1016/j.ygyno.2013.07.107

M3 - Journal article

C2 - 23917080

SN - 0090-8258

VL - 131

SP - 8

EP - 14

JO - Gynecologic Oncology

JF - Gynecologic Oncology

IS - 1

ER -

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

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