Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Cuellar-Partida, G., Lu, Y., Dixon, S.C., Australian Ovarian Cancer Study, 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., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W., Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Blake Gilks, C., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., Goode, E.L., Schildkraut, J.M., Pearce, C.L., Berchuck, A., Pharoah, P.D.P., Webb, P.M., Chenevix-Trench, G., Risch, H.A. and MacGregor, S. (2016) Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Human Genetics, 135 7: 741-756. doi:10.1007/s00439-016-1663-9


Author Cuellar-Partida, G.
Lu, Y.
Dixon, S.C.
Australian Ovarian Cancer Study
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.
Dork, T.
Durst, M.
Hillemanns, P.
Runnebaum, I.B.
Antonenkova, N.
Butzow, R.
Leminen, A.
Nevanlinna, H.
Pelttari, L.M.
Edwards, R.P.
Kelley, J.L.
Modugno, F.
Moysich, K.B.
Ness, R.B.
Cannioto, R.
Hogdall, E.
Hogdall, C.
Jensen, A.
Giles, G.G.
Bruinsma, F.
Kjaer, S.K.
Hildebrandt, M.A.T.
Liang, D.
Lu, K.H.
Wu, X.
Bisogna, M.
Dao, F.
Levine, D.A.
Cramer, D.W.
Terry, K.L.
Tworoger, S.S.
Stampfer, M.
Missmer, S.
Bjorge, L.
Salvesen, H.B.
Kopperud, R.K.
Bischof, K.
Aben, K.K.H.
Kiemeney, L.A.
Massuger, L.F.A.G.
Brooks-Wilson, A.
Olson, S.H.
McGuire, V.
Rothstein, J.H.
Sieh, W.
Whittemore, A.S.
Cook, L.S.
Le, N.D.
Blake Gilks, C.
Gronwald, J.
Jakubowska, A.
Lubinski, J.
Kluz, T.
Song, H.
Tyrer, J.P.
Wentzensen, N.
Brinton, L.
Trabert, B.
Lissowska, J.
McLaughlin, J.R.
Narod, S.A.
Phelan, C.
Anton-Culver, H.
Ziogas, A.
Eccles, D.
Campbell, I.
Gayther, S.A.
Gentry-Maharaj, A.
Menon, U.
Ramus, S.J.
Wu, A.H.
Dansonka-Mieszkowska, A.
Kupryjanczyk, J.
Timorek, A.
Szafron, L.
Cunningham, J.M.
Fridley, B.L.
Winham, S.J.
Bandera, E.V.
Poole, E.M.
Morgan, T.K.
Goode, E.L.
Schildkraut, J.M.
Pearce, C.L.
Berchuck, A.
Pharoah, P.D.P.
Webb, P.M.
Chenevix-Trench, G.
Risch, H.A.
MacGregor, S.
Title Assessing the genetic architecture of epithelial ovarian cancer histological subtypes
Journal name Human Genetics   Check publisher's open access policy
ISSN 1432-1203
0340-6717
Publication date 2016-07-01
Year available 2016
Sub-type Article (original research)
DOI 10.1007/s00439-016-1663-9
Open Access Status Not Open Access
Volume 135
Issue 7
Start page 741
End page 756
Total pages 16
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
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 ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 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.
Formatted 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 ( h2ghg2 = 8.8 ± 1.1 %), endometrioid ( h2ghg2 = 3.2 ± 1.6 %), clear cell ( h2ghg2 = 6.7 ± 3.3 %) and all EOC ( h2ghg2 = 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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 CA050385
R01 CA087538
P01 CA087969
R01 CA067262
P30 CA046592
P30 CA072720
UL1 TR001863
R03 CA113148
R01 CA058598
R01 CA058860
R01 CA074850
R01 CA063678
K07 CA092044
P30 CA008748
P30 CA014089
R01 CA054419
R01 CA122443
R01 CA149429
10119
R01 CA049449
R01 CA063682
R01 CA112523
P50 CA136393
R01 CA126841
R01 CA114343
10124
Institutional Status UQ

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