Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Feng, H.L.; Gusev, A.; Pasaniuc, B.; Wu, L.; Long, J.R.; Abu-full, Z.; ... ; OCGN Investigators (2020)

Article / Letter to editor

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

• breast cancer subtype
• causal gene
• GWAS
• TWAS

• All authors: Feng, H.L.; Gusev, A.; Pasaniuc, B.; Wu, L.; Long, J.R.; Abu-full, Z.; Aittomaki, K.; Andrulis, I.L.; Anton-Culver, H.; Antoniou, A.C.; Arason, A.; Arndt, V.; Aronson, K.J.; Arun, B.K.; Asseryanis, E.; Auer, P.L.; Azzollini, J.; Balmana, J.; Barkardottir, R.B.; Barnes, D.R.; Barrowdale, D.; Beckmann, M.W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Bialkowska, K.; Blanco, A.; Blomqvist, C.; Boeckx, B.; Bogdanova, N.V.; Bojesen, S.E.; Bolla, M.K.; Bonanni, B.; Borg, A.; Brauch, H.; Brenner, H.; Briceno, I.; Broeks, A.; Bruning, T.; Burwinkel, B.; Cai, Q.Y.; Caldes, T.; Caligo, M.A.; Campbell, I.; Canisius, S.; Campa, D.; Carter, B.D.; Carter, J.; Castelao, J.E.; Chang-Claude, J.; Chanock, S.J.; Christiansen, H.; Chung, W.K.; Claes, K.B.M.; Clarke, C.L.; Couch, F.J.; Cox, A.; Cross, S.S.; Cybulski, C.; Czene, K.; Daly, M.B.; Hoya, M. de la; Leeneer, K. de; Dennis, J.; Devilee, P.; Diez, O.; Domchek, S.M.; Dork, T.; dos-Santos-Silva, I.; Dunning, A.M.; Dwek, M.; Eccles, D.M.; Ejlertsen, B.; Ellberg, C.; Engel, C.; Eriksson, M.; Fasching, P.A.; Fletcher, O.; Flyger, H.; Fostira, F.; Friedman, E.; Fritschi, L.; Frost, D.; Gabrielson, M.; Ganz, P.A.; Gapstur, S.M.; Garber, J.; Garcia-Closas, M.; Garcia-Saenz, J.A.; Gaudet, M.M.; Giles, G.G.; Glendon, G.; Godwin, A.K.; Goldberg, M.S.; Goldgar, D.E.; Gonzalez-Neira, A.; Greene, M.H.; Gronwald, J.; Guenel, P.; Haiman, C.A.; Hall, P.; Hamann, U.; Hake, C.; He, W.; Heyworth, J.; Hogervorst, F.B.L.; Hollestelle, A.; Hooning, M.J.; Hoover, R.N.; Hopper, J.L.; Huang, G.M.Q.; Hulick, P.J.; Humphreys, K.; Imyanitov, E.N.; Isaacs, C.; Jakimovska, M.; Jakubowska, A.; James, P.; Janavicius, R.; Jankowitz, R.C.; John, E.M.; Johnson, N.; Joseph, V.; Jung, A.R.; Karlan, B.Y.; Khusnutdinova, E.; Kiiski, J.I.; Konstantopoulou, I.; Kristensen, V.N.; Laitman, Y.; Lambrechts, D.; Lazaro, C.; Leroux, D.; Leslie, G.; Lester, J.; Lesueur, F.; Lindor, N.; Lindstrom, S.; W.Y. lo; Loud, J.T.; Lubinski, J.; Makalic, E.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martens, J.W.M.; Martinez, M.E.; Matricardi, L.; Maurer, T.; Mavroudis, D.; McGuffog, L.; Meindl, A.; Menon, U.; Michailidou, K.; Kapoor, P.M.; Miller, A.; Montagna, M.; Moreno, F.; Moserle, L.; Mulligan, A.M.; Muranen, T.A.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Nevelsteen, I.; Nielsen, F.C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O.I.; Olsson, H.; Osorio, A.; Papp, J.; Park-Simon, T.W.; Parsons, M.T.; Pedersen, I.S.; Peixoto, A.; Peterlongo, P.; Peto, J.; Pharoah, P.D.P.; Phillips, K.A.; Plaseska-Karanfilska, D.; Poppe, B.; Pradhan, N.; Prajzendanc, K.; Presneau, N.; Punie, K.; Pylkas, K.; Radice, P.; Rantala, J.; Rashid, M.U.; Rennert, G.; Risch, H.A.; Robson, M.; Romero, A.; Saloustros, E.; Sandler, D.P.; Santos, C.; Sawyer, E.J.; Schmidt, M.K.; Schmidt, D.F.; Schmutzler, R.K.; Schoemaker, M.J.; Scott, R.J.; Sharma, P.; Shu, X.O.; Simard, J.; Singer, C.F.; Skytte, A.B.; Soucy, P.; Southey, M.C.; Spinelli, J.J.; Spurdle, A.B.; Stone, J.; Swerdlow, A.J.; Tapper, W.J.; Taylor, J.A.; Teixeira, M.R.; Terry, M.B.; Teule, A.; Thomassen, M.; Thone, K.; Thull, D.L.; Tischkowitz, M.; Toland, A.E.; Tollenaar, R.A.E.M.; Torres, D.; Truong, T.; Tung, N.D.; Vachon, C.M.; Asperen, C.J. van; Ouweland, A.M.W. van den; Rensburg, E.J. van; Vega, A.; Viel, A.; Vieiro-Balo, P.; Wang, Q.; Wappenschmidt, B.; Weinberg, C.R.; Weitzel, J.N.; Wendt, C.; Winqvist, R.; Yang, X.H.R.; Yannoukakos, D.; Ziogas, A.; Milne, R.L.; Easton, D.F.; Chenevix-Trench, G.; Zheng, W.; Kraft, P.; Jiang, X.; GEMO Study Collaborators; EMBRACE Collaborators; GC-HBOC Study Collaborators; ABCTB Investigators; HEBON Investigators; BCFR Investigators; OCGN Investigators
• Date: 2020-03-01
• Journal: Genetic Epidemiology
• Volume: 44
• Issue: 5
• Pages: 442 - 468
• DOI: doi:10.1002/gepi.22288
• Link: https://onlinelibrary.wiley.com/doi/10.1002/gepi.22288