Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Madalene A. Earp; Linda E. Kelemen; Anthony M. Magliocco; Kenneth D. Swenerton; Georgia Chenevix-Trench; Yi Lu; Alexander Hein; Arif B. Ekici; Matthias W. Beckmann; Peter A. Fasching; Diether Lambrechts; Evelyn Despierre; Ignace Vergote; Sandrina Lambrechts; Jennifer A. Doherty; Mary Anne Rossing; Jenny Chang-Claude; Anja Rudolph; Grace Friel; Kirsten B. Moysich; Kunle Odunsi; Lara Sucheston-Campbell; Galina Lurie; Marc T. Goodman; Michael E. Carney; Pamela J. Thompson; Ingo B. Runnebaum; Matthias Dürst; Peter Hillemanns; Thilo Dörk; Natalia Antonenkova; Natalia Bogdanova; Arto Leminen; Heli Nevanlinna; Liisa M. Pelttari; Ralf Butzow; Clareann H. Bunker; Francesmary Modugno; Robert P. Edwards; Roberta B. Ness; Andreas Du Bois; Florian Heitz; Ira Schwaab; Philipp Harter; Beth Y. Karlan; Christine Walsh; Jenny Lester; Allan Jensen; Susanne K. Kjær; Claus K. Høgdall; Estrid Høgdall; Lene Lundvall; Thomas A. Sellers; Brooke L. Fridley; Ellen L. Goode; Julie M. Cunningham; Robert A. Vierkant; Graham G. Giles; Laura Baglietto; Gianluca Severi; Melissa C. Southey; Dong Liang; Xifeng Wu; Karen Lu; Michelle A.T. Hildebrandt; Douglas A. Levine; Maria Bisogna; Joellen M. Schildkraut; Edwin S. Iversen; Rachel Palmieri Weber; Andrew Berchuck; Daniel W. Cramer; Kathryn L. Terry; Elizabeth M. Poole; Shelley S. Tworoger; Elisa V. Bandera; Urmila Chandran; Irene Orlow; Sara H. Olson; Elisabeth Wik; Helga B. Salvesen; Line Bjorge; Mari K. Halle; Anne M. Van Altena; Katja K.H. Aben; Lambertus A. Kiemeney; Leon F.A.G. Massuger; Tanja Pejovic; Yukie T. Bean; Cezary Cybulski; Jacek Gronwald; Jan Lubinski; Nicolas Wentzensen; Louise A. Brinton; Jolanta Lissowska; Montserrat Garcia-Closas; Ed Dicks; Joe Dennis; Douglas F. Easton; Honglin Song; Jonathan P. Tyrer; Paul D.P. Pharoah; Diana Eccles; Ian G. Campbell; Alice S. Whittemore; Valerie McGuire; Weiva Sieh; Joseph H. Rothstein; James M. Flanagan; James Paul; Robert Brown; Catherine M. Phelan; Harvey A. Risch; John R. McLaughlin; Steven A. Narod; Argyrios Ziogas; Hoda Anton-Culver; Aleksandra Gentry-Maharaj; Usha Menon; Simon A. Gayther; Susan J. Ramus; Anna H. Wu; Celeste L. Pearce; Malcolm C. Pike; Agnieszka Dansonka-Mieszkowska; Iwona K. Rzepecka; Lukasz M. Szafron; Jolanta Kupryjanczyk; Linda S. Cook; Nhu D. Le; Angela Brooks-Wilson

doi:10.1007/s00439-013-1383-3

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Madalene A. Earp, Linda E. Kelemen, Anthony M. Magliocco, Kenneth D. Swenerton, Georgia Chenevix-Trench, Yi Lu, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer A. Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B. MoysichKunle Odunsi, Lara Sucheston-Campbell, Galina Lurie, Marc T. Goodman, Michael E. Carney, Pamela J. Thompson, Ingo B. Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Heli Nevanlinna, Liisa M. Pelttari, Ralf Butzow, Clareann H. Bunker, Francesmary Modugno, Robert P. Edwards, Roberta B. Ness, Andreas Du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Beth Y. Karlan, Christine Walsh, Jenny Lester, Allan Jensen, Susanne K. Kjær, Claus K. Høgdall, Estrid Høgdall, Lene Lundvall, Thomas A. Sellers, Brooke L. Fridley, Ellen L. Goode, Julie M. Cunningham, Robert A. Vierkant, Graham G. Giles, Laura Baglietto, Gianluca Severi, Melissa C. Southey, Dong Liang, Xifeng Wu, Karen Lu, Michelle A.T. Hildebrandt, Douglas A. Levine, Maria Bisogna, Joellen M. Schildkraut, Edwin S. Iversen, Rachel Palmieri Weber, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Elizabeth M. Poole, Shelley S. Tworoger, Elisa V. Bandera, Urmila Chandran, Irene Orlow, Sara H. Olson, Elisabeth Wik, Helga B. Salvesen, Line Bjorge, Mari K. Halle, Anne M. Van Altena, Katja K.H. Aben, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Tanja Pejovic, Yukie T. Bean, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ed Dicks, Joe Dennis, Douglas F. Easton, Honglin Song, Jonathan P. Tyrer, Paul D.P. Pharoah, Diana Eccles, Ian G. Campbell, Alice S. Whittemore, Valerie McGuire, Weiva Sieh, Joseph H. Rothstein, James M. Flanagan, James Paul, Robert Brown, Catherine M. Phelan, Harvey A. Risch, John R. McLaughlin, Steven A. Narod, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha Menon, Simon A. Gayther, Susan J. Ramus, Anna H. Wu, Celeste L. Pearce, Malcolm C. Pike, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Lukasz M. Szafron, Jolanta Kupryjanczyk, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Original language	English
Pages (from-to)	481-497
Number of pages	17
Journal	Human Genetics
Volume	133
Issue number	5
DOIs	https://doi.org/10.1007/s00439-013-1383-3
State	Published - May 2014
Externally published	Yes

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10.1007/s00439-013-1383-3

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Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., ... Brooks-Wilson, A. (2014). Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Human Genetics, 133(5), 481-497. https://doi.org/10.1007/s00439-013-1383-3

@article{9e0a94855c824d82954ad5b8ef5eb0cf,

title = "Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA",

abstract = "Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.",

author = "Earp, {Madalene A.} and Kelemen, {Linda E.} and Magliocco, {Anthony M.} and Swenerton, {Kenneth D.} and Georgia Chenevix-Trench and Yi Lu and Alexander Hein and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Fasching, {Peter A.} and Diether Lambrechts and Evelyn Despierre and Ignace Vergote and Sandrina Lambrechts and Doherty, {Jennifer A.} and Rossing, {Mary Anne} and Jenny Chang-Claude and Anja Rudolph and Grace Friel and Moysich, {Kirsten B.} and Kunle Odunsi and Lara Sucheston-Campbell and Galina Lurie and Goodman, {Marc T.} and Carney, {Michael E.} and Thompson, {Pamela J.} and Runnebaum, {Ingo B.} and Matthias D{\"u}rst and Peter Hillemanns and Thilo D{\"o}rk and Natalia Antonenkova and Natalia Bogdanova and Arto Leminen and Heli Nevanlinna and Pelttari, {Liisa M.} and Ralf Butzow and Bunker, {Clareann H.} and Francesmary Modugno and Edwards, {Robert P.} and Ness, {Roberta B.} and {Du Bois}, Andreas and Florian Heitz and Ira Schwaab and Philipp Harter and Karlan, {Beth Y.} and Christine Walsh and Jenny Lester and Allan Jensen and Kj{\ae}r, {Susanne K.} and H{\o}gdall, {Claus K.} and Estrid H{\o}gdall and Lene Lundvall and Sellers, {Thomas A.} and Fridley, {Brooke L.} and Goode, {Ellen L.} and Cunningham, {Julie M.} and Vierkant, {Robert A.} and Giles, {Graham G.} and Laura Baglietto and Gianluca Severi and Southey, {Melissa C.} and Dong Liang and Xifeng Wu and Karen Lu and Hildebrandt, {Michelle A.T.} and Levine, {Douglas A.} and Maria Bisogna and Schildkraut, {Joellen M.} and Iversen, {Edwin S.} and Weber, {Rachel Palmieri} and Andrew Berchuck and Cramer, {Daniel W.} and Terry, {Kathryn L.} and Poole, {Elizabeth M.} and Tworoger, {Shelley S.} and Bandera, {Elisa V.} and Urmila Chandran and Irene Orlow and Olson, {Sara H.} and Elisabeth Wik and Salvesen, {Helga B.} and Line Bjorge and Halle, {Mari K.} and {Van Altena}, {Anne M.} and Aben, {Katja K.H.} and Kiemeney, {Lambertus A.} and Massuger, {Leon F.A.G.} and Tanja Pejovic and Bean, {Yukie T.} and Cezary Cybulski and Jacek Gronwald and Jan Lubinski and Nicolas Wentzensen and Brinton, {Louise A.} and Jolanta Lissowska and Montserrat Garcia-Closas and Ed Dicks and Joe Dennis and Easton, {Douglas F.} and Honglin Song and Tyrer, {Jonathan P.} and Pharoah, {Paul D.P.} and Diana Eccles and Campbell, {Ian G.} and Whittemore, {Alice S.} and Valerie McGuire and Weiva Sieh and Rothstein, {Joseph H.} and Flanagan, {James M.} and James Paul and Robert Brown and Phelan, {Catherine M.} and Risch, {Harvey A.} and McLaughlin, {John R.} and Narod, {Steven A.} and Argyrios Ziogas and Hoda Anton-Culver and Aleksandra Gentry-Maharaj and Usha Menon and Gayther, {Simon A.} and Ramus, {Susan J.} and Wu, {Anna H.} and Pearce, {Celeste L.} and Pike, {Malcolm C.} and Agnieszka Dansonka-Mieszkowska and Rzepecka, {Iwona K.} and Szafron, {Lukasz M.} and Jolanta Kupryjanczyk and Cook, {Linda S.} and Le, {Nhu D.} and Angela Brooks-Wilson",

note = "Funding Information: Higher level funding: The COGS project is funded through a European Commission{\textquoteright}s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding Information: Funding of constituent studies: This project was funded through grants from the Canadian Institutes of Health Research (MOP-86727, MOP-84340); WorkSafeBC 14, and OvCaRe: BC{\textquoteright}s Ovarian Cancer Research Team. Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389 V-20170, N01-CN25403, 2II0200); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/ A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlan-gen-Nuremberg; the Eve Appeal (Oak Foundation); the Fred C. and Katherine B. Andersen Foundation; the German Cancer Research Center; the German Federal Ministry of Education and Research of Germany, Program of Clinical Biomedical Research (01 GB 9401); the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the L & S Milken Foundation; the Lon V. Smith Foundation (LVS-39420); the Mayo Foundation; the Mermaid I project; the Minnesota Ovarian Cancer Alliance; the National Health and Medical Research Council of Australia (199600, 209057, 251533, 396414, 400281, and 504715); Nationaal Kankerplan of Belgium; the Norwegian Cancer Society; the Norwegian Research Council; the OHSU Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Pomeranian Medical University; Radboud University Medical Center; the Roswell Park Cancer Institute Alliance Foundation; the Royal Marsden Hospital; the Rudolf-Bartling Foundation; the Sigrid Juselius Foundation; the state of Baden-W{\"u}rttemberg through Medical Faculty of the University of Ulm (P.685); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and the University College London Hospitals; the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280); the Department of Defense Ovarian Cancer Research Program (W81XWH-07-1-0449); the US National Cancer Institute (K07-CA095666, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966 and Intramural research funds); the US National Institutes of Health/ National Center for Research Resources/General Clinical Research Center (MO1-RR000056); and the US Public Health Service (PSA-042205). Funding Information: Investigator support: L.E.K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). G.C.-T. is supported by the National Health and Medical Research Council. B.Y. K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). F.M. is supported by a K-award from the National Cancer Institute (K07-CA080668). W.S. is supported by a K-award from the National Cancer Institute (K07-CA143047). D.F.E. is a Principal Research Fellow of Cancer Research UK.",

year = "2014",

month = may,

doi = "10.1007/s00439-013-1383-3",

language = "English",

volume = "133",

pages = "481--497",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "5",

}

Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, Du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjær, SK, Høgdall, CK, Høgdall, E, Lundvall, L, Sellers, TA, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Giles, GG, Baglietto, L, Severi, G, Southey, MC, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Levine, DA, Bisogna, M, Schildkraut, JM, Iversen, ES, Weber, RP, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Chandran, U, Orlow, I, Olson, SH, Wik, E, Salvesen, HB, Bjorge, L, Halle, MK, Van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, YT, Cybulski, C, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Garcia-Closas, M, Dicks, E, Dennis, J, Easton, DF, Song, H, Tyrer, JP, Pharoah, PDP, Eccles, D, Campbell, IG, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, JH, Flanagan, JM, Paul, J, Brown, R, Phelan, CM, Risch, HA, McLaughlin, JR, Narod, SA, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Gayther, SA, Ramus, SJ, Wu, AH, Pearce, CL, Pike, MC, Dansonka-Mieszkowska, A, Rzepecka, IK, Szafron, LM, Kupryjanczyk, J, Cook, LS, Le, ND & Brooks-Wilson, A 2014, 'Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA', Human Genetics, vol. 133, no. 5, pp. 481-497. https://doi.org/10.1007/s00439-013-1383-3

TY - JOUR

T1 - Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

AU - Earp, Madalene A.

AU - Kelemen, Linda E.

AU - Magliocco, Anthony M.

AU - Swenerton, Kenneth D.

AU - Chenevix-Trench, Georgia

AU - Lu, Yi

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Fasching, Peter A.

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Vergote, Ignace

AU - Lambrechts, Sandrina

AU - Doherty, Jennifer A.

AU - Rossing, Mary Anne

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Friel, Grace

AU - Moysich, Kirsten B.

AU - Odunsi, Kunle

AU - Sucheston-Campbell, Lara

AU - Lurie, Galina

AU - Goodman, Marc T.

AU - Carney, Michael E.

AU - Thompson, Pamela J.

AU - Runnebaum, Ingo B.

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Dörk, Thilo

AU - Antonenkova, Natalia

AU - Bogdanova, Natalia

AU - Leminen, Arto

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Butzow, Ralf

AU - Bunker, Clareann H.

AU - Modugno, Francesmary

AU - Edwards, Robert P.

AU - Ness, Roberta B.

AU - Du Bois, Andreas

AU - Heitz, Florian

AU - Schwaab, Ira

AU - Harter, Philipp

AU - Karlan, Beth Y.

AU - Walsh, Christine

AU - Lester, Jenny

AU - Jensen, Allan

AU - Kjær, Susanne K.

AU - Høgdall, Claus K.

AU - Høgdall, Estrid

AU - Lundvall, Lene

AU - Sellers, Thomas A.

AU - Fridley, Brooke L.

AU - Goode, Ellen L.

AU - Cunningham, Julie M.

AU - Vierkant, Robert A.

AU - Giles, Graham G.

AU - Baglietto, Laura

AU - Severi, Gianluca

AU - Southey, Melissa C.

AU - Liang, Dong

AU - Wu, Xifeng

AU - Lu, Karen

AU - Hildebrandt, Michelle A.T.

AU - Levine, Douglas A.

AU - Bisogna, Maria

AU - Schildkraut, Joellen M.

AU - Iversen, Edwin S.

AU - Weber, Rachel Palmieri

AU - Berchuck, Andrew

AU - Cramer, Daniel W.

AU - Terry, Kathryn L.

AU - Poole, Elizabeth M.

AU - Tworoger, Shelley S.

AU - Bandera, Elisa V.

AU - Chandran, Urmila

AU - Orlow, Irene

AU - Olson, Sara H.

AU - Wik, Elisabeth

AU - Salvesen, Helga B.

AU - Bjorge, Line

AU - Halle, Mari K.

AU - Van Altena, Anne M.

AU - Aben, Katja K.H.

AU - Kiemeney, Lambertus A.

AU - Massuger, Leon F.A.G.

AU - Pejovic, Tanja

AU - Bean, Yukie T.

AU - Cybulski, Cezary

AU - Gronwald, Jacek

AU - Lubinski, Jan

AU - Wentzensen, Nicolas

AU - Brinton, Louise A.

AU - Lissowska, Jolanta

AU - Garcia-Closas, Montserrat

AU - Dicks, Ed

AU - Dennis, Joe

AU - Easton, Douglas F.

AU - Song, Honglin

AU - Tyrer, Jonathan P.

AU - Pharoah, Paul D.P.

AU - Eccles, Diana

AU - Campbell, Ian G.

AU - Whittemore, Alice S.

AU - McGuire, Valerie

AU - Sieh, Weiva

AU - Rothstein, Joseph H.

AU - Flanagan, James M.

AU - Paul, James

AU - Brown, Robert

AU - Phelan, Catherine M.

AU - Risch, Harvey A.

AU - McLaughlin, John R.

AU - Narod, Steven A.

AU - Ziogas, Argyrios

AU - Anton-Culver, Hoda

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Gayther, Simon A.

AU - Ramus, Susan J.

AU - Wu, Anna H.

AU - Pearce, Celeste L.

AU - Pike, Malcolm C.

AU - Dansonka-Mieszkowska, Agnieszka

AU - Rzepecka, Iwona K.

AU - Szafron, Lukasz M.

AU - Kupryjanczyk, Jolanta

AU - Cook, Linda S.

AU - Le, Nhu D.

AU - Brooks-Wilson, Angela

N1 - Funding Information: Higher level funding: The COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding Information: Funding of constituent studies: This project was funded through grants from the Canadian Institutes of Health Research (MOP-86727, MOP-84340); WorkSafeBC 14, and OvCaRe: BC’s Ovarian Cancer Research Team. Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389 V-20170, N01-CN25403, 2II0200); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/ A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlan-gen-Nuremberg; the Eve Appeal (Oak Foundation); the Fred C. and Katherine B. Andersen Foundation; the German Cancer Research Center; the German Federal Ministry of Education and Research of Germany, Program of Clinical Biomedical Research (01 GB 9401); the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the L & S Milken Foundation; the Lon V. Smith Foundation (LVS-39420); the Mayo Foundation; the Mermaid I project; the Minnesota Ovarian Cancer Alliance; the National Health and Medical Research Council of Australia (199600, 209057, 251533, 396414, 400281, and 504715); Nationaal Kankerplan of Belgium; the Norwegian Cancer Society; the Norwegian Research Council; the OHSU Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Pomeranian Medical University; Radboud University Medical Center; the Roswell Park Cancer Institute Alliance Foundation; the Royal Marsden Hospital; the Rudolf-Bartling Foundation; the Sigrid Juselius Foundation; the state of Baden-Württemberg through Medical Faculty of the University of Ulm (P.685); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and the University College London Hospitals; the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280); the Department of Defense Ovarian Cancer Research Program (W81XWH-07-1-0449); the US National Cancer Institute (K07-CA095666, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966 and Intramural research funds); the US National Institutes of Health/ National Center for Research Resources/General Clinical Research Center (MO1-RR000056); and the US Public Health Service (PSA-042205). Funding Information: Investigator support: L.E.K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). G.C.-T. is supported by the National Health and Medical Research Council. B.Y. K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). F.M. is supported by a K-award from the National Cancer Institute (K07-CA080668). W.S. is supported by a K-award from the National Cancer Institute (K07-CA143047). D.F.E. is a Principal Research Fellow of Cancer Research UK.

PY - 2014/5

Y1 - 2014/5

N2 - Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

AB - Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

UR - http://www.scopus.com/inward/record.url?scp=84899620671&partnerID=8YFLogxK

U2 - 10.1007/s00439-013-1383-3

DO - 10.1007/s00439-013-1383-3

M3 - Article

C2 - 24190013

AN - SCOPUS:84899620671

SN - 0340-6717

VL - 133

SP - 481

EP - 497

JO - Human Genetics

JF - Human Genetics

IS - 5

ER -

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Abstract

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