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Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

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Figure 1: Histotype-specific associations (odds ratios) of the top SNP in 12 new EOC susceptibility regions.
Figure 2: Number of overlaps between candidate causal SNPs and H3K27ac in relevant tissues and cell lines.
Figure 3: Functional analysis of the 10q24.33 locus.

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Acknowledgements

The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.). Funding sources for the contributing studies are provided in the Supplementary Note.

We pay special tribute to the contribution of Brian Henderson to the GAME-ON consortium and to Olga M. Sinilnikova for her contribution to CIMBA and for her part in the initiation and coordination of GEMO until she sadly passed away on 30 June 2014. We thank the study participants, doctors, nurses, clinical and scientific collaborators, healthcare providers and health information sources that have contributed to the many studies contributing to this manuscript. A full list is provided in the Supplementary Note.

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Writing group: C.M.P., K.B.K., J.P.T., S.P.K., K.L., S.J.W., D.H., M.A.E., A.N.M., G.C.-T., E.L.G., S.J.R., T.A.S., S.A.G., A.C.A., P.D.P.P. Coordination of OCAC OncoArray genotyping: C.M.P., M.J.R., G.C. Coordination of CIMBA OncoArray genotyping: G.C.-T., L.M., J.S., P. Soucy. OncoArray genotyping: CIDR (M.A., T.S., K.F.D., J. Romm, E.P.), Mayo (J.M.C.), UCam (C. Luccarini). OncoArray genotype calling and quality control: K.B.K., D.F.E., J.D., D.B., E.D., A. Pirie, A. Lee, J.L., G.L. Statistical analyses for OCAC: J.P.T., P.D.P.P. Statistical analyses for CIMBA: K.B.K., A. Lee, A.C.A. Meta-analyses: K.B.K., A.C.A. OCAC database management: M.J.R., A. Berchuck. CIMBA database management and BRCA1 and BRCA2 variant nomenclature and classification: L.M., G.L., A.B.S. Supervision of OCAC statistical analyses: P.D.P.P. Supervision of CIMBA statistical analyses: A.C.A. Conceiving and coordination of the synthesis of the OncoArray: P.D.P.P., D.F.E., C.I.A., S. Chanock, S.G., D.J.H., A.C.A., J.S. Functional analyses: P.C.L., S. Coetzee, M.A.E., S.A.G., E.L.G., D.H., S.P.K., K.L., J.M.L, G.M.-F., A.N.M., S.J.W., G.C.-T., J. Beesley. Provision of DNA samples and/or phenotypic data: C.M.A., K.K.H.A., J. Adlard, I.L.A., H.A.-C., N. Antonenkova, G.A., N. Arnold, B.K.A., B.A., J. Azzollini, J. Balmaña, S.N.B., L. Barjhoux, R.B.B., Y.B., M.W.B., A.B.-F., J. Benitez, A. Berchuck, M. Bermisheva, M.Q. Bernardini, M.J. Birrer, L. Bjorge, A. Black, K. Blankstein, M.J. Blok, C. Bodelon, N.B., A. Bojesen, B. Bonanni, ñ. Borg, A.R.B., J.D.B., C. Brewer, L. Brinton, P.B., A.B.-W., F.B., J. Brunet, B. Buecher, R.B., S.S.B., T. Caldes, M.A.C., I.C., R.C., M.E.C., T. Cescon, S.B.C., J.C.-C., X.Q.C., G.C-T., Y.-E.C., J. Chiquette, W.K.C., K.B.M.C., T. Conner, J. Cook, L.S.C., F.J.C., D.W.C., A.A.D., M.B.D., F. Damiola, S.D.D., A.D., F. Dao, R.D., A.d.F., C.D., O.D., Y.C.D., J.A.D., S.M.D., C.M.D., T.D., L.D., M. Duran, M. Dürst, B.D., D.E., T.E., R.E., U.E., B.E., A.B.E., S.E., M.E., K.H.E., C.E., D.G.E., P.A.F., S.F., S.F.F., J.M.F., T.M.F., Z.C.F., R.T.F., F.F., W.D.F., G.F., B.L.F., E.F., D.F., P.A.G., J. Garber, M.J.G., V.G.-B., S.A.G., A.G., A.G.-M., A.-M.G., G.G.G. R.G., G. Glendon, A.K.G., D.E.G., E.L.G., M.T.G., T.G., M.G., M.H.G., J. Gronwald, E. Hahnen, C.A.H., N.H., U.H., T.V.O.H., P.A.H., H.R.H., J. Hauke, A. Hein, A. Henderson, M.A.T.H., P.H., S.H., C.K.H., E. Høgdall, F.B.L.H., H.H., M.J.H., K.H., R.-Y.H., P.J.H., J. Hung, D.G.H., T.H., E.N.I., C.I., E.S.I., L.I., A.I., A. Jakubowska, P.J., R.J., A. Jensen, M.J., U.B.J., E.M.J., S.J., M.E.J., P.K., B.Y.K., A. Karzenis, K.K., L.E.K., C.J.K., E.K., L.A.K., J.I.K., S.-W.K., S.K.K., M.K., R.K.K., T.A.K., J.K., A. Kwong, Y.L., D. Lambrechts, N.L., M.C.L., C. Lazaro, N.D.L., L.L.M., J.W.L., S.B.L., A. Leminen, D. Leroux, J. Lester, F.L., D.A.L., D. Liang, C. Liebrich, J. Lilyquist, L. Lipworth, J. Lissowska, K.H.L., J. Lubinński, L. Lundvall, P.L.M., S. Manoukian, L.F.A.G.M., T.M., S. Mazoyer, J.N.M., V.M., J.R.M., I.M., H.M.-H., A.M., U.M., A.R.M., M.A. Merritt, R.L.M., G.M., F.M., J.M.-S., M. Moffitt, M. Montagna, K.B.M., A.M.M., J.M., S.A.N., K.L.N., L.N., R.B.N., S.L.N., H.N., D.N., R.L.N., K. Odunsi, K. Offit, E.O., O.I.O., H.O., C.O., D.M.O'M., K.O., N.C.O.-M., N.O., S.O., A.O., L.O., D.P., L. Papi, S.K.P., T.-W.P.-S., J.P., C.L.P., I.S.P., P.H.M.P., B. Peissel, A. Peixoto, T. Pejovic, L.M.P., J.B.P., P. Peterlongo, L.P., G.P., P.D.P.P., C.M.P., K.-A.P., M.P., M.C.P., A.M.P., S.R.P., T. Pocza, E.M.P., B. Poppe, M.E.P., F.P., D. Palli, D. Prokofyeva, M.A.P., P. Pujol, P. Radice, S.J.R., J. Rantala, C.R.-F., G.R., K.R., P. Rice, A. Richardson, H.A.R., M.R., G.C.R., C.R.-A., M.A. Rookus, M.A. Rossing, J.H.R., A. Rudolph, I.B.R., H.B.S., D.P.S., J.M.S., R.K.S., M.J.S., T.A.S., L. Senter, V.W.S., G. Severi, P. Sharma, N.S., L.E. Side, W.S., J.S., C.F.S., H. Sobol, H. Song, P. Soucy, M.S., A.B.S., Z.S., D.S., D.S.-L., L.E.S.-C., G. Sukiennicki, R.S., C.S., A.J.S., C.I.S., L. Szafron, Y.Y.T., J.A.T., M.-K.T., M.R.T., S.-H.T., K.L.T., M. Thomassen, P.J.T., L.C.V.T., D.L.T., L.T., A.V.T., M. Tischkowitz, S.T., A.E.T., A. Tone, B.T., R.T., A. Trichopoulou, N.T., S.S.T., A.M.V.A., D.V.D.B., A.H.v.d.H., R.B.v.d.L., M.V.H., E.V.N., E.J.v.R., A. Vanderstichele, R.V.-M., A. Vega, D.V.E., I.V., J.V., R.A.V., A. Vratimos, L.W., C.W., D.W., S.W.-G., B.W., P.M.W., C.R.W., J.N.W., N.W., A.S.W., J.T.W., L.R.W., A.W., M.W., A.H.W., X.W., H.Y., D.Y., A.Z., K.K.Z.

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Correspondence to Paul D P Pharoah.

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A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 Candidate target genes are altered in ovarian cancer samples.

Each locus (also indicated by the index SNP) is represented by a panel that shows genes in linear order and whether they are part of the same TAD as the top SNPs (red) or not (gray). The PubMed track indicates whether a gene has been implicated in ovarian cancer (red) or not (gray) in published papers. The amplified and deleted tracks show the percentage of cases with copy number alterations (ovarian cystadenocarcinoma; TCGA, provisional; n = 579). The histogram displays the percentage of samples in which at least one gene in the locus is altered (deletion, amplification, truncation or missense mutations). Candidate genes of interest are labeled in red font.

Supplementary Figure 2 Chromosome conformation capture interactions in ovarian cancer susceptibility loci.

Each locus (also indicated by the index SNP) shows a matrix of interactions at 25-kb resolution in HMEC cells. TAD borders (blue arrows) were manually identified as asymmetries in the interaction patterns. SNPs in the 100:1 set are shown as a red bar in the lower human genome browser track. In cases in which the 100:1 SNP set spanned more than one TAD (8q21.11, 22q12.1, 5q12.3), genes in both TADs were included (yellow highlight).

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Phelan, C., Kuchenbaecker, K., Tyrer, J. et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet 49, 680–691 (2017). https://doi.org/10.1038/ng.3826

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