Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Gabriel Cuellar-Partida; Yi Lu; Suzanne C Dixon; 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 Doerk; Matthias Durst; 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 Vilma Solyom Høgdall; Claus Høgdall; Allan Jensen; Graham Giles; Fiona Bruinsma; Susanne Krüger Kjær; 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 J 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 M 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 P D 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, 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 Doerk, Matthias DurstPeter 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 Vilma Solyom Høgdall, Claus Høgdall, Allan Jensen, Graham Giles, Fiona Bruinsma, Susanne Krüger Kjær, 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 J 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 M 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 P D Pharoah, Penelope M Webb, Georgia Chenevix-Trench, Harvey A Risch, Stuart Macgregor

Department of Clinical Medicine

15 Citations (Scopus)

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
Journal	Human Genetics
Volume	135
Issue number	7
Pages (from-to)	741-756
Number of pages	16
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-016-1663-9
Publication status	Published - 1 Jul 2016

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Cuellar-Partida, G., Lu, Y., Dixon, S. C., 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., Doerk, T., ... 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, 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, Doerk, T, Durst, 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, EVS , Høgdall, C, Jensen, A, Giles, G, Bruinsma, F, Kjær, SK, Hildebrandt, MAT, Liang, D, Lu, KH, Wu, X, Bisogna, M, Dao, F, Levine, DA, Cramer, DW, Terry, KL, Tworoger, SS, Stampfer, MJ, 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, LM, Cunningham, JM, Fridley, BL, Winham, SJ, Bandera, EV, Poole, EM, Morgan, TK, Goode, EL, Schildkraut, JM, Pearce, CL, Berchuck, A, Pharoah, PPD, 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

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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.",

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year = "2016",

month = jul,

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

language = "English",

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pages = "741--756",

journal = "Human Genetics",

issn = "0340-6717",

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

AU - Cuellar-Partida, Gabriel

AU - Lu, Yi

AU - Dixon, Suzanne C

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 - Doerk, Thilo

AU - Durst, 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 Vilma Solyom

AU - Høgdall, Claus

AU - Jensen, Allan

AU - Giles, Graham

AU - Bruinsma, Fiona

AU - Kjær, Susanne Krüger

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 J

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 M

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 P D

AU - Webb, Penelope M

AU - Chenevix-Trench, Georgia

AU - Risch, Harvey A

AU - Macgregor, Stuart

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.

U2 - 10.1007/s00439-016-1663-9

DO - 10.1007/s00439-016-1663-9

M3 - Journal article

C2 - 27075448

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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