Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Gabriel Cuellar-Partida; Yi Lu; Suzanne C. Dixon; Ovarian Cancer Study Australian Ovarian Cancer Study; Peter A. Fasching; Alexander Hein; Stefanie Burghaus; Matthias W. Beckmann; Diether Lambrechts; Els Van Nieuwenhuysen; Ignace Vergote; Adriaan Vanderstichele; Jennifer Anne Doherty; Mary Anne Rossing; Jenny Chang-Claude; Anja Rudolph; Shan Wang-Gohrke; Marc T. Goodman; Natalia Bogdanova; Thilo Dörk; Matthias Dürst; Peter Hillemanns; Ingo B. Runnebaum; Natalia Antonenkova; Ralf Butzow; Arto Leminen; Heli Nevanlinna; Liisa M. Pelttari; Robert P. Edwards; Joseph L. Kelley; Francesmary Modugno; Kirsten B. Moysich; Roberta B. Ness; Rikki Cannioto; Estrid Høgdall; Claus Høgdall; Allan Jensen; Graham G. Giles; Fiona Bruinsma; Susanne K. Kjaer; Michelle A.T. Hildebrandt; Dong Liang; Karen H. Lu; Xifeng Wu; Maria Bisogna; Fanny Dao; Douglas A. Levine; Daniel W. Cramer; Kathryn L. Terry; Shelley S. Tworoger; Meir Stampfer; Stacey Missmer; Line Bjorge; Helga B. Salvesen; Reidun K. Kopperud; Katharina Bischof; Katja K.H. Aben; Lambertus A. Kiemeney; Leon F.A.G. Massuger; Angela Brooks-Wilson; Sara H. Olson; Valerie McGuire; Joseph H. Rothstein; Weiva Sieh; Alice S. Whittemore; Linda S. Cook; Nhu D. Le; C. Blake Gilks; Jacek Gronwald; Anna Jakubowska; Jan Lubiński; Tomasz Kluz; Honglin Song; Jonathan P. Tyrer; Nicolas Wentzensen; Louise Brinton; Britton Trabert; Jolanta Lissowska; John R. McLaughlin; Steven A. Narod; Catherine Phelan; Hoda Anton-Culver; Argyrios Ziogas; Diana Eccles; Ian Campbell; Simon A. Gayther; Aleksandra Gentry-Maharaj; Usha Menon; Susan J. Ramus; Anna H. Wu; Agnieszka Dansonka-Mieszkowska; Jolanta Kupryjanczyk; Agnieszka Timorek; Lukasz Szafron; Julie M. Cunningham; Brooke L. Fridley; Stacey J. Winham; Elisa V. Bandera; Elizabeth M. Poole; Terry K. Morgan; Ellen L. Goode; Joellen M. Schildkraut; Celeste L. Pearce; Andrew Berchuck; Paul D.P. Pharoah; Penelope M. Webb; Georgia Chenevix-Trench; Harvey A. Risch; Stuart MacGregor

doi:10.1007/s00439-016-1663-9

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Gabriel Cuellar-Partida, Yi Lu, Suzanne C. Dixon, Ovarian Cancer Study Australian Ovarian Cancer Study, Peter A. Fasching, Alexander Hein, Stefanie Burghaus, Matthias W. Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Adriaan Vanderstichele, Jennifer Anne Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Shan Wang-Gohrke, Marc T. Goodman, Natalia Bogdanova, Thilo DörkMatthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Natalia Antonenkova, Ralf Butzow, Arto Leminen, Heli Nevanlinna, Liisa M. Pelttari, Robert P. Edwards, Joseph L. Kelley, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Rikki Cannioto, Estrid Høgdall, Claus Høgdall, Allan Jensen, Graham G. Giles, Fiona Bruinsma, Susanne K. Kjaer, Michelle A.T. Hildebrandt, Dong Liang, Karen H. Lu, Xifeng Wu, Maria Bisogna, Fanny Dao, Douglas A. Levine, Daniel W. Cramer, Kathryn L. Terry, Shelley S. Tworoger, Meir Stampfer, Stacey Missmer, Line Bjorge, Helga B. Salvesen, Reidun K. Kopperud, Katharina Bischof, Katja K.H. Aben, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Angela Brooks-Wilson, Sara H. Olson, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Alice S. Whittemore, Linda S. Cook, Nhu D. Le, C. Blake Gilks, Jacek Gronwald, Anna Jakubowska, Jan Lubiński, Tomasz Kluz, Honglin Song, Jonathan P. Tyrer, Nicolas Wentzensen, Louise Brinton, Britton Trabert, Jolanta Lissowska, John R. McLaughlin, Steven A. Narod, Catherine Phelan, Hoda Anton-Culver, Argyrios Ziogas, Diana Eccles, Ian Campbell, Simon A. Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Susan J. Ramus, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Agnieszka Timorek, Lukasz Szafron, Julie M. Cunningham, Brooke L. Fridley, Stacey J. Winham, Elisa V. Bandera, Elizabeth M. Poole, Terry K. Morgan, Ellen L. Goode, Joellen M. Schildkraut, Celeste L. Pearce, Andrew Berchuck, Paul D.P. Pharoah, Penelope M. Webb, Georgia Chenevix-Trench, Harvey A. Risch, Stuart MacGregor

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

17 Scopus citations

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Original language	English (US)
Pages (from-to)	741-756
Number of pages	16
Journal	Human genetics
Volume	135
Issue number	7
DOIs	https://doi.org/10.1007/s00439-016-1663-9
State	Published - Jul 1 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1007/s00439-016-1663-9

Cite this

Cuellar-Partida, G., Lu, Y., Dixon, S. C., Australian Ovarian Cancer Study, O. C. S., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., ... MacGregor, S. (2016). Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Human genetics, 135(7), 741-756. https://doi.org/10.1007/s00439-016-1663-9

Cuellar-Partida, G, Lu, Y, Dixon, SC, Australian Ovarian Cancer Study, OCS, Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, Pelttari, LM, Edwards, RP, Kelley, JL, Modugno, F, Moysich, KB, Ness, RB, Cannioto, R, Høgdall, E, Høgdall, C, Jensen, A, Giles, GG, Bruinsma, F, Kjaer, SK, Hildebrandt, MAT, Liang, D, Lu, KH, Wu, X, Bisogna, M, Dao, F, Levine, DA, Cramer, DW, Terry, KL, Tworoger, SS, Stampfer, M, Missmer, S, Bjorge, L, Salvesen, HB, Kopperud, RK, Bischof, K, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Brooks-Wilson, A, Olson, SH, McGuire, V, Rothstein, JH, Sieh, W, Whittemore, AS, Cook, LS, Le, ND, Blake Gilks, C, Gronwald, J, Jakubowska, A, Lubiński, J, Kluz, T, Song, H, Tyrer, JP, Wentzensen, N, Brinton, L, Trabert, B, Lissowska, J, McLaughlin, JR, Narod, SA, Phelan, C, Anton-Culver, H, Ziogas, A, Eccles, D, Campbell, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Wu, AH, Dansonka-Mieszkowska, A, Kupryjanczyk, J, Timorek, A, Szafron, L, Cunningham, JM, Fridley, BL, Winham, SJ, Bandera, EV, Poole, EM, Morgan, TK, Goode, EL, Schildkraut, JM, Pearce, CL, Berchuck, A, Pharoah, PDP, Webb, PM, Chenevix-Trench, G, Risch, HA & MacGregor, S 2016, 'Assessing the genetic architecture of epithelial ovarian cancer histological subtypes', Human genetics, vol. 135, no. 7, pp. 741-756. https://doi.org/10.1007/s00439-016-1663-9

@article{9338b397ff4948638b810e69779fbad0,

title = "Assessing the genetic architecture of epithelial ovarian cancer histological subtypes",

abstract = "Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.",

author = "Gabriel Cuellar-Partida and Yi Lu and Dixon, {Suzanne C.} and {Australian Ovarian Cancer Study}, {Ovarian Cancer Study} and Fasching, {Peter A.} and Alexander Hein and Stefanie Burghaus and Beckmann, {Matthias W.} and Diether Lambrechts and {Van Nieuwenhuysen}, Els and Ignace Vergote and Adriaan Vanderstichele and Doherty, {Jennifer Anne} and Rossing, {Mary Anne} and Jenny Chang-Claude and Anja Rudolph and Shan Wang-Gohrke and Goodman, {Marc T.} and Natalia Bogdanova and Thilo D{\"o}rk and Matthias D{\"u}rst and Peter Hillemanns and Runnebaum, {Ingo B.} and Natalia Antonenkova and Ralf Butzow and Arto Leminen and Heli Nevanlinna and Pelttari, {Liisa M.} and Edwards, {Robert P.} and Kelley, {Joseph L.} and Francesmary Modugno and Moysich, {Kirsten B.} and Ness, {Roberta B.} and Rikki Cannioto and Estrid H{\o}gdall and Claus H{\o}gdall and Allan Jensen and Giles, {Graham G.} and Fiona Bruinsma and Kjaer, {Susanne K.} and Hildebrandt, {Michelle A.T.} and Dong Liang and Lu, {Karen H.} and Xifeng Wu and Maria Bisogna and Fanny Dao and Levine, {Douglas A.} and Cramer, {Daniel W.} and Terry, {Kathryn L.} and Tworoger, {Shelley S.} and Meir Stampfer and Stacey Missmer and Line Bjorge and Salvesen, {Helga B.} and Kopperud, {Reidun K.} and Katharina Bischof and Aben, {Katja K.H.} and Kiemeney, {Lambertus A.} and Massuger, {Leon F.A.G.} and Angela Brooks-Wilson and Olson, {Sara H.} and Valerie McGuire and Rothstein, {Joseph H.} and Weiva Sieh and Whittemore, {Alice S.} and Cook, {Linda S.} and Le, {Nhu D.} and {Blake Gilks}, C. and Jacek Gronwald and Anna Jakubowska and Jan Lubi{\'n}ski and Tomasz Kluz and Honglin Song and Tyrer, {Jonathan P.} and Nicolas Wentzensen and Louise Brinton and Britton Trabert and Jolanta Lissowska and McLaughlin, {John R.} and Narod, {Steven A.} and Catherine Phelan and Hoda Anton-Culver and Argyrios Ziogas and Diana Eccles and Ian Campbell and Gayther, {Simon A.} and Aleksandra Gentry-Maharaj and Usha Menon and Ramus, {Susan J.} and Wu, {Anna H.} and Agnieszka Dansonka-Mieszkowska and Jolanta Kupryjanczyk and Agnieszka Timorek and Lukasz Szafron and Cunningham, {Julie M.} and Fridley, {Brooke L.} and Winham, {Stacey J.} and Bandera, {Elisa V.} and Poole, {Elizabeth M.} and Morgan, {Terry K.} and Goode, {Ellen L.} and Schildkraut, {Joellen M.} and Pearce, {Celeste L.} and Andrew Berchuck and Pharoah, {Paul D.P.} and Webb, {Penelope M.} and Georgia Chenevix-Trench and Risch, {Harvey A.} and Stuart MacGregor",

note = "Funding Information: 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 Nurses{\textquoteright} Health Studies would like to thank the participants and staff of the Nurses{\textquoteright} Health Study and Nurses{\textquoteright} Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; 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); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, 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-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital {\textquoteleft}Womens Health Theme{\textquoteright} and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y. L. was supported by the NHMRC Early Career Fellowship. G. C. T. is supported by the National Health and Medical Research Council. S. M. was supported by an ARC Future Fellowship. Funding Information: 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 Nurses{\^a} Health Studies would like to thank the participants and staff of the Nurses{\^a} Health Study and Nurses{\^a} Health Study II{\^A} for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; 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); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, 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-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01{\^A} GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme{\^a} and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y. L. was supported by the NHMRC Early Career Fellowship. G. C. T. is supported by the National Health and Medical Research Council. S. M. was supported by an ARC Future Fellowship. Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg.",

year = "2016",

month = jul,

day = "1",

doi = "10.1007/s00439-016-1663-9",

language = "English (US)",

volume = "135",

pages = "741--756",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Verlag",

number = "7",

}

TY - JOUR

T1 - Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

AU - Cuellar-Partida, Gabriel

AU - Lu, Yi

AU - Dixon, Suzanne C.

AU - Australian Ovarian Cancer Study, Ovarian Cancer Study

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Burghaus, Stefanie

AU - Beckmann, Matthias W.

AU - Lambrechts, Diether

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Vanderstichele, Adriaan

AU - Doherty, Jennifer Anne

AU - Rossing, Mary Anne

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Wang-Gohrke, Shan

AU - Goodman, Marc T.

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B.

AU - Antonenkova, Natalia

AU - Butzow, Ralf

AU - Leminen, Arto

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Ness, Roberta B.

AU - Cannioto, Rikki

AU - Høgdall, Estrid

AU - Høgdall, Claus

AU - Jensen, Allan

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Kjaer, Susanne K.

AU - Hildebrandt, Michelle A.T.

AU - Liang, Dong

AU - Lu, Karen H.

AU - Wu, Xifeng

AU - Bisogna, Maria

AU - Dao, Fanny

AU - Levine, Douglas A.

AU - Cramer, Daniel W.

AU - Terry, Kathryn L.

AU - Tworoger, Shelley S.

AU - Stampfer, Meir

AU - Missmer, Stacey

AU - Bjorge, Line

AU - Salvesen, Helga B.

AU - Kopperud, Reidun K.

AU - Bischof, Katharina

AU - Aben, Katja K.H.

AU - Kiemeney, Lambertus A.

AU - Massuger, Leon F.A.G.

AU - Brooks-Wilson, Angela

AU - Olson, Sara H.

AU - McGuire, Valerie

AU - Rothstein, Joseph H.

AU - Sieh, Weiva

AU - Whittemore, Alice S.

AU - Cook, Linda S.

AU - Le, Nhu D.

AU - Blake Gilks, C.

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Lubiński, Jan

AU - Kluz, Tomasz

AU - Song, Honglin

AU - Tyrer, Jonathan P.

AU - Wentzensen, Nicolas

AU - Brinton, Louise

AU - Trabert, Britton

AU - Lissowska, Jolanta

AU - McLaughlin, John R.

AU - Narod, Steven A.

AU - Phelan, Catherine

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Eccles, Diana

AU - Campbell, Ian

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Ramus, Susan J.

AU - Wu, Anna H.

AU - Dansonka-Mieszkowska, Agnieszka

AU - Kupryjanczyk, Jolanta

AU - Timorek, Agnieszka

AU - Szafron, Lukasz

AU - Cunningham, Julie M.

AU - Fridley, Brooke L.

AU - Winham, Stacey J.

AU - Bandera, Elisa V.

AU - Poole, Elizabeth M.

AU - Morgan, Terry K.

AU - Goode, Ellen L.

AU - Schildkraut, Joellen M.

AU - Pearce, Celeste L.

AU - Berchuck, Andrew

AU - Pharoah, Paul D.P.

AU - Webb, Penelope M.

AU - Chenevix-Trench, Georgia

AU - Risch, Harvey A.

AU - MacGregor, Stuart

N1 - Funding Information: 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 Nurses’ Health Studies would like to thank the participants and staff of the Nurses’ Health Study and Nurses’ Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; 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); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, 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-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital ‘Womens Health Theme’ and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y. L. was supported by the NHMRC Early Career Fellowship. G. C. T. is supported by the National Health and Medical Research Council. S. M. was supported by an ARC Future Fellowship. Funding Information: 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 Nursesâ Health Studies would like to thank the participants and staff of the Nursesâ Health Study and Nursesâ Health Study IIÂ for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; 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); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, 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-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01Â GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Themeâ and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y. L. was supported by the NHMRC Early Career Fellowship. G. C. T. is supported by the National Health and Medical Research Council. S. M. was supported by an ARC Future Fellowship. Publisher Copyright: © 2016, Springer-Verlag Berlin Heidelberg.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

AB - Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

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U2 - 10.1007/s00439-016-1663-9

DO - 10.1007/s00439-016-1663-9

M3 - Article

C2 - 27075448

AN - SCOPUS:84963682858

SN - 0340-6717

VL - 135

SP - 741

EP - 756

JO - Human Genetics

JF - Human Genetics

IS - 7

ER -

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

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