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
Publication date 2016-07
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
Collection year 2017
Language eng
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.
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