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1. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands

Author

Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), Yntema, H.G., Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), and Yntema, H.G.

Abstract

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Published
2017
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2. Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Author

Haer-Wigman, L. (Lonneke), Zelst-Stams, W.A. van, Pfundt, R. (Rolph), Born, L.I. (Ingeborgh) van den, Klaver, C.C.W. (Caroline), Verheij, J.B. (Joke), Hoyng, C.B. (Carel), Breuning, M.H. (Martijn), Boon, C.J.F. (Camiel), Kievit, A.J.A. (Anneke J.A.), Verhoeven, V.J.M. (Virginie), Pott, J.W.R., Sallevelt, S.C.E.H. (Suzanne), Hagen, J.M. (Johanna) van, Plomp, A. (Astrid), Kroes, H.Y. (Hester), Lelieveld, S.H. (Stefan H.), Hehir-Kwa, J. (Jayne), Castelein, S. (Steven), Nelen, M.R. (Marcel), Scheffer, H. (Hans), Lugtenberg, D. (Dorien), Cremers, F.P.M. (Frans), Hoefsloot, E.H. (Lies), Yntema, H.G., Haer-Wigman, L. (Lonneke), Zelst-Stams, W.A. van, Pfundt, R. (Rolph), Born, L.I. (Ingeborgh) van den, Klaver, C.C.W. (Caroline), Verheij, J.B. (Joke), Hoyng, C.B. (Carel), Breuning, M.H. (Martijn), Boon, C.J.F. (Camiel), Kievit, A.J.A. (Anneke J.A.), Verhoeven, V.J.M. (Virginie), Pott, J.W.R., Sallevelt, S.C.E.H. (Suzanne), Hagen, J.M. (Johanna) van, Plomp, A. (Astrid), Kroes, H.Y. (Hester), Lelieveld, S.H. (Stefan H.), Hehir-Kwa, J. (Jayne), Castelein, S. (Steven), Nelen, M.R. (Marcel), Scheffer, H. (Hans), Lugtenberg, D. (Dorien), Cremers, F.P.M. (Frans), Hoefsloot, E.H. (Lies), and Yntema, H.G.

Abstract

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

Published
2017
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3. Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Author

Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), Cuppen, E. (Edwin), Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), and Cuppen, E. (Edwin)

Abstract

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Published
2015
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4. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: Results from a multicenter study

Author

Jakubowska, A. (Anna), Rozkrut, D. (D.), Antoniou, A.C. (Antonis), Hamann, U. (Ute), Scott, R.J. (Rodney), McGuffog, L. (Lesley), Healy, S. (S.), Sinilnikova, O. (Olga), Rennert, G. (Gad), Lejbkowicz, F. (Flavio), Flugelman, A. (Anath), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Paligo, M. (M.), Aretini, P. (Paolo), Kantala, J. (J.), Aroer, B. (B.), Wachenfeldt, A. (Anna) von, Liljegren, A. (Annelie), Loman, N. (Niklas), Herbst, H., Kristoffersson, U. (Ulf), Rosenquist, R. (R.), Karlsson, P. (Per), Stenmark-Askmalm, M. (M.), Melin, B. (Beatrice), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Byrski, T. (Tomasz), Huzarski, T. (Tomasz), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Cybulski, C. (Cezary), Serrano, P. (Pedro), Osorio, A. (Ana), Cajal, T.R., Tsitlaidou, M. (M.), Benítez, J. (Javier), Gilbert, M. (Michel), Rookus, M.A. (Matti), Aalfs, C.M. (Cora), Kluijt, I. (Irma), Boessenkool-Pape, J.L. (J.), Meijers-Heijboer, E.J. (Hanne), Oosterwijk, J.C. (Jan), Asperen, C.J. (Christi) van, Blok, M.J. (Marinus), Nelen, M.R. (Marcel), Ouweland, A.M.W. (Ans) van den, Seynaeve, C.M. (Caroline), Luijt, R.B. (Rob) van der, Devilee, P. (Peter), Easton, D.F. (Douglas), Peock, S. (Susan), Frost, D. (Debra), Platte, R. (Radka), Ellis, S.D. (Steve), Fineberg, E. (Elena), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Jacobs, C. (Chris), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T.J. (Trevor), Cook, J. (Jackie), Godwin, A.K. (Andrew), Bove, B. (B.), Stoppa-Lyonnet, D. (Dominique), Caux-Moncoutier, V. (Virginie), Belotti, M. (Muriel), Tirapo, C. (Carole), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Boutry-Kryza, N. (N.), Pujol, P. (Pascal), Coupier, I. (Isabelle), Peyrat, J.-P., Vennin, P. (Philippe), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Vénat-Bouvet, L. (Laurence), Johannson, O.T. (Oskar), Isaacs, C. (Claudine), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Arnold, N. (Norbert), Varon-Mateeva, R. (Raymonda), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Preisler-Adams, S. (Sabine), Simard, J. (Jacques), Soucy, P. (Penny), Durocher, F. (Francine), Chenevix-Trench, G. (Georgia), Beesley, J. (Jonathan), Chen, X.C. (X. C.), Rebbeck, R. (Timothy), Couch, F.J. (Fergus), Wang, X. (Xing), Lindor, N.M. (Noralane), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Peterlongo, P. (Paolo), Bonnani, B. (Bernardo), Fortuzzi, S. (S.), Peissel, B. (Bernard), Szabo, C. (Csilla), Mai, P.L. (Phuong), Loud, J.T. (Jennifer), Lubinski, J. (Jan), Jakubowska, A. (Anna), Rozkrut, D. (D.), Antoniou, A.C. (Antonis), Hamann, U. (Ute), Scott, R.J. (Rodney), McGuffog, L. (Lesley), Healy, S. (S.), Sinilnikova, O. (Olga), Rennert, G. (Gad), Lejbkowicz, F. (Flavio), Flugelman, A. (Anath), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Paligo, M. (M.), Aretini, P. (Paolo), Kantala, J. (J.), Aroer, B. (B.), Wachenfeldt, A. (Anna) von, Liljegren, A. (Annelie), Loman, N. (Niklas), Herbst, H., Kristoffersson, U. (Ulf), Rosenquist, R. (R.), Karlsson, P. (Per), Stenmark-Askmalm, M. (M.), Melin, B. (Beatrice), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Byrski, T. (Tomasz), Huzarski, T. (Tomasz), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Cybulski, C. (Cezary), Serrano, P. (Pedro), Osorio, A. (Ana), Cajal, T.R., Tsitlaidou, M. (M.), Benítez, J. (Javier), Gilbert, M. (Michel), Rookus, M.A. (Matti), Aalfs, C.M. (Cora), Kluijt, I. (Irma), Boessenkool-Pape, J.L. (J.), Meijers-Heijboer, E.J. (Hanne), Oosterwijk, J.C. (Jan), Asperen, C.J. (Christi) van, Blok, M.J. (Marinus), Nelen, M.R. (Marcel), Ouweland, A.M.W. (Ans) van den, Seynaeve, C.M. (Caroline), Luijt, R.B. (Rob) van der, Devilee, P. (Peter), Easton, D.F. (Douglas), Peock, S. (Susan), Frost, D. (Debra), Platte, R. (Radka), Ellis, S.D. (Steve), Fineberg, E. (Elena), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Jacobs, C. (Chris), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T.J. (Trevor), Cook, J. (Jackie), Godwin, A.K. (Andrew), Bove, B. (B.), Stoppa-Lyonnet, D. (Dominique), Caux-Moncoutier, V. (Virginie), Belotti, M. (Muriel), Tirapo, C. (Carole), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Boutry-Kryza, N. (N.), Pujol, P. (Pascal), Coupier, I. (Isabelle), Peyrat, J.-P., Vennin, P. (Philippe), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Vénat-Bouvet, L. (Laurence), Johannson, O.T. (Oskar), Isaacs, C. (Claudine), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Arnold, N. (Norbert), Varon-Mateeva, R. (Raymonda), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Preisler-Adams, S. (Sabine), Simard, J. (Jacques), Soucy, P. (Penny), Durocher, F. (Francine), Chenevix-Trench, G. (Georgia), Beesley, J. (Jonathan), Chen, X.C. (X. C.), Rebbeck, R. (Timothy), Couch, F.J. (Fergus), Wang, X. (Xing), Lindor, N.M. (Noralane), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Peterlongo, P. (Paolo), Bonnani, B. (Bernardo), Fortuzzi, S. (S.), Peissel, B. (Bernard), Szabo, C. (Csilla), Mai, P.L. (Phuong), Loud, J.T. (Jennifer), and Lubinski, J. (Jan)

Abstract

Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Published
2012
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5. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, A.C. (Antonis), Kartsonaki, C. (Christiana), Sinilnikova, O. (Olga), Soucy, P. (Penny), McGuffog, L. (Lesley), Healey, S. (Sue), Lee, A. (Andrew), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Barile, M. (Monica), Pensotti, V. (Valeria), Pasini, B. (Barbara), Dolcetti, R. (Riccardo), Giannini, G. (Giuseppe), Putignano, A.L., Varesco, L. (Liliana), Radice, P. (Paolo), Mai, P.L. (Phuong), Greene, M.H. (Mark), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Gerdes, A-M. (Anne-Marie), Kruse, T.A. (Torben), Jensen, U.B., Cruger, D. (Dorthe), Caligo, M.A. (Maria), Laitman, Y. (Yael), Milgrom, R. (Roni), Kaufman, B. (Bella), Paluch-Shimon, S. (Shani), Friedman, E. (Eitan), Loman, N. (Niklas), Harbst, K. (Katja), Lindblom, A. (Annika), Melin, B. (Beatrice), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Rebbeck, R. (Timothy), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Cybulski, C. (Cezary), Górski, B. (Bohdan), Osorio, A. (Ana), Cajal, T.R., Fostira, F. (Florentia), Andres, R. (Raquel), Benitez, J. (Javier), Hamann, U. (Ute), Hogervorst, F.B.L. (Frans), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Nelen, M.R. (Marcel), Luijt, R.B. (Rob) van der, Os, T.A.M. (Theo) van, Asperen, C.J. (Christi) van, Devilee, P. (Peter), Meijers-Heijboer, H. (Hanne), Garcia, E.B.G., Peock, S. (Susan), Cook, M. (Margaret), Frost, D., Platte, R. (Radka), Leyland, J. (Jean), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Davidson, R. (Rosemarie), Eccles, D. (Diana), Ong, K.-R., Douglas, F. (Fiona), Paterson, J. (Joan), Kennedy, M.J. (John), Miedzybrodzka, Z. (Zosia), Godwin, A.K. (Andrew), Stoppa-Lyonnet, D. (Dominique), Buecher, B. (Bruno), Belotti, M. (Muriel), Tirapo, C. (Carole), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Lasset, C. (Christine), Leroux, D. (Dominique), Faivre, L. (Laurence), Bronner, M. (Myriam), Prieur, F. (Fabienne), Nogues, C. (Catherine), Rouleau, E. (Etienne), Pujol, P. (Pascal), Coupier, I. (Isabelle), Frenay, M. (Marc), Hopper, J. (John), Daly, M.J. (Mark), Terry, M-B. (Mary-beth), John, E.M. (Esther), Buys, S.S. (Saundra), Yassin, Y. (Yosuf), Miron, A. (Alexander), Goldgar, D. (David), Singer, C.F. (Christian), Tea, M.-K., Pfeiler, G. (Georg), Dressler, C. (Catherina), Hansen, T.V.O. (Thomas), Jønson, L. (Lars), Ejlertsen, B. (Bent), Barkardottir, R.B. (Rosa), Kircchoff, T. (Tomas), Offit, K. (Kenneth), Piedmonte, M. (Marion), Rodriguez, G.C. (Gustavo), Small, L. (Laurie), Boggess, J.F. (John), Blank, S.V. (Stephanie), Basil, J. (Jack), Azodi, M. (Masoud), Toland, A.E. (Amanda), Montagna, M. (Marco), Tognazzo, S. (Silvia), Agata, S. (Simona), Imyanitov, E.N. (Evgeny), Janavicius, R. (Ramunas), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Pharoah, P.D.P. (Paul), Sucheston, L. (Lara), Karlan, B.Y. (Beth), Walsh, C.S. (Christine), Olah, E. (Edith), Bozsik, A. (Aniko), Teo, S.-H. (Soo-Hwang), Seldon, J.L. (Joyce), Beattie, M.S. (Mary), Rensburg, E.J. (Elizabeth) van, Sluiter, M.D. (Michelle), Diez, O. (Orland), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Varon-Mateeva, R. (Raymonda), Kast, K. (Karin), Deissler, H. (Helmut), Niederacher, D. (Dieter), Arnold, N. (Norbert), Gadzicki, D. (Dorothea), Schönbuchner, I. (Ines), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Dumont, M. (Martine), Chiquette, J. (Jocelyne), Tischkowitz, M. (Marc), Chenevix-Trench, G. (Georgia), Beesley, J. (Jonathan), Spurdle, A.B. (Amanda), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Fredericksen, Z. (Zachary), Wang, X. (Xing), Pankratz, V.S. (Shane), Couch, F.J. (Fergus), Simard, J. (Jacques), Easton, D.F. (Douglas), Karlsson, P. (Per), Nordling, M. (Margareta), Bergman, A. (Annika), Einbeigi, Z. (Zakaria), Stenmark-Askmalm, M. (M.), Liedgren, S. (Sigrun), Borg, Å. (Åke), Olsson, H. (Hans), Kristoffersson, U. (Ulf), Jernström, H. (H.), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Liljegren, A. (Annelie), Barbany-Bustinza, G. (Gisela), Rantala, J. (Johanna), Grönberg, H. (Henrik), Stattin, E.-L., Emanuelsson, M. (Monica), Brandell, R.R., Dahl, N. (Niklas), Verhoef, S., Verheus, M. (Martijn), Veer, L.J. (Laura) van 't, Leeuwen, F.E. (Flora) van, Collée, J.M. (Margriet), Ouweland, A.M.W. (Ans) van den, Jager, A. (Agnes), Tilanus-Linthorst, M.M.A. (Madeleine), Seynaeve, C.M. (Caroline), Wijnen, J.T. (Juul), Vreeswijk, M.P. (Maaike), Tollenaar, R.A.E.M. (Rob), Ligtenberg, M.J. (Marjolijn), Hoogerbrugge, N. (Nicoline), Ausems, M.G.E.M. (Margreet), Aalfs, C.M. (Cora), Gille, J.J.P. (Jan), Waisfisz, Q. (Quinten), Gómez García, E.B. (Encarna), Roozendaal, C.E. (Cees) van, Blok, M.J. (Marinus), Caanen, B., Oosterwijk, J.C., Hout, A.H. (Annemarie) van der, Mourits, M.J., Vasen, H.F. (Hans), Gregory, H. (Helen), Morrison, P.J. (Patrick), Jeffers, L. (Lisa), Cole, T.J. (Trevor), McKeown, C. (Carole), Hoffman, J. (Jonathan), Donaldson, A. (Alan), Downing, S. (Sarah), Taylor, A. (Amy), Murray, A. (Alexandra), Rogers, M.T. (Mark), McCann, E. (Emma), Porteous, M.E. (Mary), Drummond, S. (Sarah), Brewer, C. (Carole), Kivuva, E. (Emma), Searle, A. (Anne), Goodman, S. (Selina), Hill, K. (Kathryn), Murday, V. (Victoria), Bradshaw, N. (Nicola), Snadden, L. (Lesley), Longmuir, M. (Mark), Watt, C. (Catherine), Gibson, S. (Sarah), Haque, E. (Eshika), Tobias, E. (Ed), Duncan, A. (Alexis), Jacobs, C. (Chris), Langman, C. (Caroline), Whaite, A. (Anna), Dorkins, H. (Huw), Barwell, J. (Julian), Chu, C. (Chengbin), Miller, J. (Julie), Ellis, I.O. (Ian), Houghton, C. (Catherine), Side, L. (Lucy), Male, A. (Alison), Berlin, C. (Cheryl), Eason, J. (Jacqueline), Collier, R. (Rebecca), Claber, O. (Oonagh), Jobson, I. (Irene), Walker, L.J. (Lisa), McLeod, D. (Diane), Halliday, D. (Dorothy), Durell, S. (Sarah), Stayner, B. (Barbara), Shanley, S. (Susan), Rahman, N. (Nazneen), Houlston, R. (Richard), Bancroft, E.K. (Elizabeth), D'Mello, L. (Lucia), Page, E. (Elizabeth), Ardern-Jones, A. (Audrey), Kohut, K. (Kelly), Wiggins, J. (Jennifer), Castro, E. (Elena), Mitra, A. (Anita), Robertson, L. (Lisa), Quarrell, O. (Oliver), Bardsley, C. (Cathryn), Ehrencrona, H. (Hans), Hodgson, S.V. (Shirley), Barton, D.E. (David), Goff, S. (Sheila), Brice, G. (Glen), Winchester, L. (Lizzie), Eddy, C. (Charlotte), Tripathi, V. (Vishakha), Attard, V. (Virginia), Lucassen, A. (Anneke), Crawford, G. (Gillian), McBride, D. (Donna), Smalley, S. (Sarah), Adlard, J.W. (Julian), Arver, B. (Brita Wasteson), Antoniou, A.C. (Antonis), Kartsonaki, C. (Christiana), Sinilnikova, O. (Olga), Soucy, P. (Penny), McGuffog, L. (Lesley), Healey, S. (Sue), Lee, A. (Andrew), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Barile, M. (Monica), Pensotti, V. (Valeria), Pasini, B. (Barbara), Dolcetti, R. (Riccardo), Giannini, G. (Giuseppe), Putignano, A.L., Varesco, L. (Liliana), Radice, P. (Paolo), Mai, P.L. (Phuong), Greene, M.H. (Mark), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Gerdes, A-M. (Anne-Marie), Kruse, T.A. (Torben), Jensen, U.B., Cruger, D. (Dorthe), Caligo, M.A. (Maria), Laitman, Y. (Yael), Milgrom, R. (Roni), Kaufman, B. (Bella), Paluch-Shimon, S. (Shani), Friedman, E. (Eitan), Loman, N. (Niklas), Harbst, K. (Katja), Lindblom, A. (Annika), Melin, B. (Beatrice), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Rebbeck, R. (Timothy), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Cybulski, C. (Cezary), Górski, B. (Bohdan), Osorio, A. (Ana), Cajal, T.R., Fostira, F. (Florentia), Andres, R. (Raquel), Benitez, J. (Javier), Hamann, U. (Ute), Hogervorst, F.B.L. (Frans), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Nelen, M.R. (Marcel), Luijt, R.B. (Rob) van der, Os, T.A.M. (Theo) van, Asperen, C.J. (Christi) van, Devilee, P. (Peter), Meijers-Heijboer, H. (Hanne), Garcia, E.B.G., Peock, S. (Susan), Cook, M. (Margaret), Frost, D., Platte, R. (Radka), Leyland, J. (Jean), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Davidson, R. (Rosemarie), Eccles, D. (Diana), Ong, K.-R., Douglas, F. (Fiona), Paterson, J. (Joan), Kennedy, M.J. (John), Miedzybrodzka, Z. (Zosia), Godwin, A.K. (Andrew), Stoppa-Lyonnet, D. (Dominique), Buecher, B. (Bruno), Belotti, M. (Muriel), Tirapo, C. (Carole), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Lasset, C. (Christine), Leroux, D. (Dominique), Faivre, L. (Laurence), Bronner, M. (Myriam), Prieur, F. (Fabienne), Nogues, C. (Catherine), Rouleau, E. (Etienne), Pujol, P. (Pascal), Coupier, I. (Isabelle), Frenay, M. (Marc), Hopper, J. (John), Daly, M.J. (Mark), Terry, M-B. (Mary-beth), John, E.M. (Esther), Buys, S.S. (Saundra), Yassin, Y. (Yosuf), Miron, A. (Alexander), Goldgar, D. (David), Singer, C.F. (Christian), Tea, M.-K., Pfeiler, G. (Georg), Dressler, C. (Catherina), Hansen, T.V.O. (Thomas), Jønson, L. (Lars), Ejlertsen, B. (Bent), Barkardottir, R.B. (Rosa), Kircchoff, T. (Tomas), Offit, K. (Kenneth), Piedmonte, M. (Marion), Rodriguez, G.C. (Gustavo), Small, L. (Laurie), Boggess, J.F. (John), Blank, S.V. (Stephanie), Basil, J. (Jack), Azodi, M. (Masoud), Toland, A.E. (Amanda), Montagna, M. (Marco), Tognazzo, S. (Silvia), Agata, S. (Simona), Imyanitov, E.N. (Evgeny), Janavicius, R. (Ramunas), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Pharoah, P.D.P. (Paul), Sucheston, L. (Lara), Karlan, B.Y. (Beth), Walsh, C.S. (Christine), Olah, E. (Edith), Bozsik, A. (Aniko), Teo, S.-H. (Soo-Hwang), Seldon, J.L. (Joyce), Beattie, M.S. (Mary), Rensburg, E.J. (Elizabeth) van, Sluiter, M.D. (Michelle), Diez, O. (Orland), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Varon-Mateeva, R. (Raymonda), Kast, K. (Karin), Deissler, H. (Helmut), Niederacher, D. (Dieter), Arnold, N. (Norbert), Gadzicki, D. (Dorothea), Schönbuchner, I. (Ines), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Dumont, M. (Martine), Chiquette, J. (Jocelyne), Tischkowitz, M. (Marc), Chenevix-Trench, G. (Georgia), Beesley, J. (Jonathan), Spurdle, A.B. (Amanda), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Fredericksen, Z. (Zachary), Wang, X. (Xing), Pankratz, V.S. (Shane), Couch, F.J. (Fergus), Simard, J. (Jacques), Easton, D.F. (Douglas), Karlsson, P. (Per), Nordling, M. (Margareta), Bergman, A. (Annika), Einbeigi, Z. (Zakaria), Stenmark-Askmalm, M. (M.), Liedgren, S. (Sigrun), Borg, Å. (Åke), Olsson, H. (Hans), Kristoffersson, U. (Ulf), Jernström, H. (H.), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Liljegren, A. (Annelie), Barbany-Bustinza, G. (Gisela), Rantala, J. (Johanna), Grönberg, H. (Henrik), Stattin, E.-L., Emanuelsson, M. (Monica), Brandell, R.R., Dahl, N. (Niklas), Verhoef, S., Verheus, M. (Martijn), Veer, L.J. (Laura) van 't, Leeuwen, F.E. (Flora) van, Collée, J.M. (Margriet), Ouweland, A.M.W. (Ans) van den, Jager, A. (Agnes), Tilanus-Linthorst, M.M.A. (Madeleine), Seynaeve, C.M. (Caroline), Wijnen, J.T. (Juul), Vreeswijk, M.P. (Maaike), Tollenaar, R.A.E.M. (Rob), Ligtenberg, M.J. (Marjolijn), Hoogerbrugge, N. (Nicoline), Ausems, M.G.E.M. (Margreet), Aalfs, C.M. (Cora), Gille, J.J.P. (Jan), Waisfisz, Q. (Quinten), Gómez García, E.B. (Encarna), Roozendaal, C.E. (Cees) van, Blok, M.J. (Marinus), Caanen, B., Oosterwijk, J.C., Hout, A.H. (Annemarie) van der, Mourits, M.J., Vasen, H.F. (Hans), Gregory, H. (Helen), Morrison, P.J. (Patrick), Jeffers, L. (Lisa), Cole, T.J. (Trevor), McKeown, C. (Carole), Hoffman, J. (Jonathan), Donaldson, A. (Alan), Downing, S. (Sarah), Taylor, A. (Amy), Murray, A. (Alexandra), Rogers, M.T. (Mark), McCann, E. (Emma), Porteous, M.E. (Mary), Drummond, S. (Sarah), Brewer, C. (Carole), Kivuva, E. (Emma), Searle, A. (Anne), Goodman, S. (Selina), Hill, K. (Kathryn), Murday, V. (Victoria), Bradshaw, N. (Nicola), Snadden, L. (Lesley), Longmuir, M. (Mark), Watt, C. (Catherine), Gibson, S. (Sarah), Haque, E. (Eshika), Tobias, E. (Ed), Duncan, A. (Alexis), Jacobs, C. (Chris), Langman, C. (Caroline), Whaite, A. (Anna), Dorkins, H. (Huw), Barwell, J. (Julian), Chu, C. (Chengbin), Miller, J. (Julie), Ellis, I.O. (Ian), Houghton, C. (Catherine), Side, L. (Lucy), Male, A. (Alison), Berlin, C. (Cheryl), Eason, J. (Jacqueline), Collier, R. (Rebecca), Claber, O. (Oonagh), Jobson, I. (Irene), Walker, L.J. (Lisa), McLeod, D. (Diane), Halliday, D. (Dorothy), Durell, S. (Sarah), Stayner, B. (Barbara), Shanley, S. (Susan), Rahman, N. (Nazneen), Houlston, R. (Richard), Bancroft, E.K. (Elizabeth), D'Mello, L. (Lucia), Page, E. (Elizabeth), Ardern-Jones, A. (Audrey), Kohut, K. (Kelly), Wiggins, J. (Jennifer), Castro, E. (Elena), Mitra, A. (Anita), Robertson, L. (Lisa), Quarrell, O. (Oliver), Bardsley, C. (Cathryn), Ehrencrona, H. (Hans), Hodgson, S.V. (Shirley), Barton, D.E. (David), Goff, S. (Sheila), Brice, G. (Glen), Winchester, L. (Lizzie), Eddy, C. (Charlotte), Tripathi, V. (Vishakha), Attard, V. (Virginia), Lucassen, A. (Anneke), Crawford, G. (Gillian), McBride, D. (Donna), Smalley, S. (Sarah), Adlard, J.W. (Julian), and Arver, B. (Brita Wasteson)

Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2= 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10-9for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10-8for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Published
2011
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6. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Mulligan, A.M. (Anna Marie), Couch, F.J. (Fergus), Barrowdale, D. (Daniel), Domchek, S.M. (Susan), Eccles, D. (Diana), Nevanlinna, H. (Heli), Ramus, S.J. (Susan), Robson, M. (Mark), Sherman, M.E. (Mark), Spurdle, A.B. (Amanda), Wapenschmidt, B. (Barbara), Lee, A. (Andrew), McGuffog, L. (Lesley), Healey, S. (Sue), Sinilnikova, O. (Olga), Janavicius, R. (Ramunas), Hansen, T.V.O. (Thomas), Nielsen, F.C. (Finn), Ejlertsen, B. (Bent), Osorio, A. (Ana), Muñoz-Repeto, I. (Iván), Durán, M. (Mercedes), Godino, J. (Javier), Pertesi, M. (Maroulio), Benítez, J. (Javier), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Bonnani, B. (Bernardo), Viel, A. (Alessandra), Pasini, B. (Barbara), Papi, L. (Laura), Ottini, L. (Laura), Savarese, A. (Antonella), Bernard, L. (Loris), Radice, P. (Paolo), Hamann, U. (Ute), Verheus, M. (Martijn), Meijers-Heijboer, E.J. (Hanne), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Nelen, M.R. (Marcel), Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), Tilanus-Linthorst, M.M.A. (Madeleine), Luijt, R.B. (Rob) van der, Os, T.V. (Theo), Rookus, M.A. (Matti), Frost, D. (Debra), Jones, J.L. (J Louise), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Cook, J. (Jackie), Donaldson, A. (Alan), Dorkins, H. (Huw), Gregory, H. (Helen), Eason, J. (Jacqueline), Houghton, C. (Catherine), Barwell, J. (Julian), Side, L. (Lucy), McCann, E. (Emma), Murray, A. (Alexandra), Peock, S. (Susan), Godwin, A.K. (Andrew), Schmutzler, R.K. (Rita), Rhiem, K. (Kerstin), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Arnold, N. (Norbert), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Gadzicki, D. (Dorothea), Kast, K. (Karin), Preisler-Adams, S. (Sabine), Varon-Mateeva, R. (Raymonda), Schoenbuchner, I. (Ines), Fiebig, B. (Britta), Heinritz, W. (Wolfram), Schäfer, D. (Dieter), Gevensleben, H. (Heidrun), Caux-Moncoutier, V. (Virginie), Fassy-Colcombet, M. (Marion), Cornelis, F. (Franco̧is), Mazoyer, S. (Sylvie), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Hardouin, A. (Agnès), Berthet, P. (Pascaline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Mortemousque, I. (Isabelle), Pujol, P. (Pascal), Coupier, I. (Isabelle), Lebrun, M. (Marine), Kientz, C. (Caroline), Longy, M. (Michel), Sevenet, N. (Nicolas), Stoppa-Lyonnet, D. (Dominique), Isaacs, C. (Claudine), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Barkardottir, R.B. (Rosa), Soucy, P. (Penny), Dumont, M. (Martine), Simard, J. (Jacques), Montagna, M. (Marco), Tognazzo, S. (Silvia), D'Andrea, E. (Emma), Fox, S.B. (Stephen), Yan, M. (Max), Rebbeck, R. (Timothy), Olopade, O.I. (Olofunmilayo), Weitzel, J.N. (Jeffrey), Lynch, H. (Henry), Ganz, P.A. (Patricia), Tomlinson, G. (Gail), Wang, X. (Xing), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Lindor, N.M. (Noralane), Szabo, C. (Csilla), Offit, K. (Kenneth), Sakr, R. (Rita), Gaudet, M.M. (Mia), Bhatia, K.P. (Kailash), Kauff, N. (Noah), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Mai, P.L. (Phuong), Greene, M.H. (Mark), Imyanitov, E.N. (Evgeny), O'Malley, F.P. (Frances), Ozcelik, H. (Hilmi), Glendon, G. (Gord), Toland, A.E. (Amanda), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Kruse, T.A. (Torben), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Soller, M. (Maria), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Arver, B. (Brita Wasteson), Stenmark-Askmalm, M. (M.), Karlsson, P. (Per), Ding, Y.C. (Yuan), Neuhausen, S.L. (Susan), Beattie, M.S. (Mary), Pharoah, P.D.P. (Paul), Moysich, K.B. (Kirsten), Nathanson, K.L. (Katherine), Karlan, B.Y. (Beth), Gross, J. (Jenny), John, E.M. (Esther), Daly, M.B. (Mary), Buys, S.S. (Saundra), Southey, M.C. (Melissa), Hopper, J.L. (John), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), Miron, A. (Alexander), Goldgar, D. (David), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Andrulis, I.L. (Irene), Antoniou, A.C. (Antonis), Mulligan, A.M. (Anna Marie), Couch, F.J. (Fergus), Barrowdale, D. (Daniel), Domchek, S.M. (Susan), Eccles, D. (Diana), Nevanlinna, H. (Heli), Ramus, S.J. (Susan), Robson, M. (Mark), Sherman, M.E. (Mark), Spurdle, A.B. (Amanda), Wapenschmidt, B. (Barbara), Lee, A. (Andrew), McGuffog, L. (Lesley), Healey, S. (Sue), Sinilnikova, O. (Olga), Janavicius, R. (Ramunas), Hansen, T.V.O. (Thomas), Nielsen, F.C. (Finn), Ejlertsen, B. (Bent), Osorio, A. (Ana), Muñoz-Repeto, I. (Iván), Durán, M. (Mercedes), Godino, J. (Javier), Pertesi, M. (Maroulio), Benítez, J. (Javier), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Bonnani, B. (Bernardo), Viel, A. (Alessandra), Pasini, B. (Barbara), Papi, L. (Laura), Ottini, L. (Laura), Savarese, A. (Antonella), Bernard, L. (Loris), Radice, P. (Paolo), Hamann, U. (Ute), Verheus, M. (Martijn), Meijers-Heijboer, E.J. (Hanne), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Nelen, M.R. (Marcel), Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), Tilanus-Linthorst, M.M.A. (Madeleine), Luijt, R.B. (Rob) van der, Os, T.V. (Theo), Rookus, M.A. (Matti), Frost, D. (Debra), Jones, J.L. (J Louise), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Cook, J. (Jackie), Donaldson, A. (Alan), Dorkins, H. (Huw), Gregory, H. (Helen), Eason, J. (Jacqueline), Houghton, C. (Catherine), Barwell, J. (Julian), Side, L. (Lucy), McCann, E. (Emma), Murray, A. (Alexandra), Peock, S. (Susan), Godwin, A.K. (Andrew), Schmutzler, R.K. (Rita), Rhiem, K. (Kerstin), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Arnold, N. (Norbert), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Gadzicki, D. (Dorothea), Kast, K. (Karin), Preisler-Adams, S. (Sabine), Varon-Mateeva, R. (Raymonda), Schoenbuchner, I. (Ines), Fiebig, B. (Britta), Heinritz, W. (Wolfram), Schäfer, D. (Dieter), Gevensleben, H. (Heidrun), Caux-Moncoutier, V. (Virginie), Fassy-Colcombet, M. (Marion), Cornelis, F. (Franco̧is), Mazoyer, S. (Sylvie), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Hardouin, A. (Agnès), Berthet, P. (Pascaline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Mortemousque, I. (Isabelle), Pujol, P. (Pascal), Coupier, I. (Isabelle), Lebrun, M. (Marine), Kientz, C. (Caroline), Longy, M. (Michel), Sevenet, N. (Nicolas), Stoppa-Lyonnet, D. (Dominique), Isaacs, C. (Claudine), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Barkardottir, R.B. (Rosa), Soucy, P. (Penny), Dumont, M. (Martine), Simard, J. (Jacques), Montagna, M. (Marco), Tognazzo, S. (Silvia), D'Andrea, E. (Emma), Fox, S.B. (Stephen), Yan, M. (Max), Rebbeck, R. (Timothy), Olopade, O.I. (Olofunmilayo), Weitzel, J.N. (Jeffrey), Lynch, H. (Henry), Ganz, P.A. (Patricia), Tomlinson, G. (Gail), Wang, X. (Xing), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Lindor, N.M. (Noralane), Szabo, C. (Csilla), Offit, K. (Kenneth), Sakr, R. (Rita), Gaudet, M.M. (Mia), Bhatia, K.P. (Kailash), Kauff, N. (Noah), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Mai, P.L. (Phuong), Greene, M.H. (Mark), Imyanitov, E.N. (Evgeny), O'Malley, F.P. (Frances), Ozcelik, H. (Hilmi), Glendon, G. (Gord), Toland, A.E. (Amanda), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Kruse, T.A. (Torben), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Soller, M. (Maria), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Arver, B. (Brita Wasteson), Stenmark-Askmalm, M. (M.), Karlsson, P. (Per), Ding, Y.C. (Yuan), Neuhausen, S.L. (Susan), Beattie, M.S. (Mary), Pharoah, P.D.P. (Paul), Moysich, K.B. (Kirsten), Nathanson, K.L. (Katherine), Karlan, B.Y. (Beth), Gross, J. (Jenny), John, E.M. (Esther), Daly, M.B. (Mary), Buys, S.S. (Saundra), Southey, M.C. (Melissa), Hopper, J.L. (John), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), Miron, A. (Alexander), Goldgar, D. (David), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Andrulis, I.L. (Irene), and Antoniou, A.C. (Antonis)

Abstract

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models

Published
2011
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7. A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder

Author

Zwaag, B. (Bert) van der, Staal, W.G. (Wouter), Hochstenbach, R. (Ron), Poot, M. (Martin), Spierenburg, H.A. (Henk), Jonge, M.V. (Maretha) de, Verbeek, N.E. (Nienke), Slot, R. (Ruben) van 't, Es, M.A. (Michael) van, Freitag, C.M. (Christine), Buizer-Voskamp, J.E. (Jacobine), Nelen, M.R. (Marcel), Berg, L.H. (Leonard) van den, Ploos van Amstel, H.K. (Hans), Engeland, H. (Herman) van, Burbach, J.P.H. (Peter), Zwaag, B. (Bert) van der, Staal, W.G. (Wouter), Hochstenbach, R. (Ron), Poot, M. (Martin), Spierenburg, H.A. (Henk), Jonge, M.V. (Maretha) de, Verbeek, N.E. (Nienke), Slot, R. (Ruben) van 't, Es, M.A. (Michael) van, Freitag, C.M. (Christine), Buizer-Voskamp, J.E. (Jacobine), Nelen, M.R. (Marcel), Berg, L.H. (Leonard) van den, Ploos van Amstel, H.K. (Hans), Engeland, H. (Herman) van, and Burbach, J.P.H. (Peter)

Abstract

High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94%in patients vs. 0.42%controls, P=0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.

Published
2010
Full Text
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8. A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder

Author

Zwaag, B. (Bert) van der, Staal, W.G. (Wouter), Hochstenbach, R. (Ron), Poot, M. (Martin), Spierenburg, H.A. (Henk), Jonge, M.V. (Maretha) de, Verbeek, N.E. (Nienke), Slot, R. (Ruben) van 't, Es, M.A. (Michael) van, Freitag, C.M. (Christine), Buizer-Voskamp, J.E. (Jacobine), Nelen, M.R. (Marcel), Berg, L.H. (Leonard) van den, Ploos van Amstel, H.K. (Hans), Engeland, H. (Herman) van, Burbach, J.P.H. (Peter), Zwaag, B. (Bert) van der, Staal, W.G. (Wouter), Hochstenbach, R. (Ron), Poot, M. (Martin), Spierenburg, H.A. (Henk), Jonge, M.V. (Maretha) de, Verbeek, N.E. (Nienke), Slot, R. (Ruben) van 't, Es, M.A. (Michael) van, Freitag, C.M. (Christine), Buizer-Voskamp, J.E. (Jacobine), Nelen, M.R. (Marcel), Berg, L.H. (Leonard) van den, Ploos van Amstel, H.K. (Hans), Engeland, H. (Herman) van, and Burbach, J.P.H. (Peter)

Abstract

High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94%in patients vs. 0.42%controls, P=0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.

Published
2010
Full Text
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