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Human Genetics

, Volume 130, Issue 5, pp 685–699 | Cite as

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

  • Kate M. Im
  • Tomas Kirchhoff
  • Xianshu Wang
  • Todd Green
  • Clement Y. Chow
  • Joseph Vijai
  • Joshua Korn
  • Mia M. Gaudet
  • Zachary Fredericksen
  • V. Shane Pankratz
  • Candace Guiducci
  • Andrew Crenshaw
  • Lesley McGuffog
  • Christiana Kartsonaki
  • Jonathan Morrison
  • Sue Healey
  • Olga M. Sinilnikova
  • Phuong L. Mai
  • Mark H. Greene
  • Marion Piedmonte
  • Wendy S. Rubinstein
  • HEBON
  • Frans B. Hogervorst
  • Matti A. Rookus
  • J. Margriet Collée
  • Nicoline Hoogerbrugge
  • Christi J. van Asperen
  • Hanne E. J. Meijers-Heijboer
  • Cees E. Van Roozendaal
  • Trinidad Caldes
  • Pedro Perez-Segura
  • Anna Jakubowska
  • Jan Lubinski
  • Tomasz Huzarski
  • Paweł Blecharz
  • Heli Nevanlinna
  • Kristiina Aittomäki
  • Conxi Lazaro
  • Ignacio Blanco
  • Rosa B. Barkardottir
  • Marco Montagna
  • Emma D’Andrea
  • kConFab
  • Peter Devilee
  • Olufunmilayo I. Olopade
  • Susan L. Neuhausen
  • Bernard Peissel
  • Bernardo Bonanni
  • Paolo Peterlongo
  • Christian F. Singer
  • Gad Rennert
  • Flavio Lejbkowicz
  • Irene L. Andrulis
  • Gord Glendon
  • Hilmi Ozcelik
  • Ontario Cancer Genetics Network
  • Amanda Ewart Toland
  • Maria Adelaide Caligo
  • SWE-BRCA
  • Mary S. Beattie
  • Salina Chan
  • UKFOCR
  • Susan M. Domchek
  • Katherine L. Nathanson
  • Timothy R. Rebbeck
  • Catherine Phelan
  • Steven Narod
  • Esther M. John
  • John L. Hopper
  • Saundra S. Buys
  • Mary B. Daly
  • Melissa C. Southey
  • Mary-Beth Terry
  • Nadine Tung
  • Thomas v. O. Hansen
  • Ana Osorio
  • Javier Benitez
  • Mercedes Durán
  • Jeffrey N. Weitzel
  • Judy Garber
  • Ute Hamann
  • EMBRACE
  • Susan Peock
  • Margaret Cook
  • Clare T. Oliver
  • Debra Frost
  • Radka Platte
  • D. Gareth Evans
  • Ros Eeles
  • Louise Izatt
  • Joan Paterson
  • Carole Brewer
  • Shirley Hodgson
  • Patrick J. Morrison
  • Mary Porteous
  • Lisa Walker
  • Mark T. Rogers
  • Lucy E. Side
  • Andrew K. Godwin
  • Rita K. Schmutzler
  • Barbara Wappenschmidt
  • Yael Laitman
  • Alfons Meindl
  • Helmut Deissler
  • Raymonda Varon-Mateeva
  • Sabine Preisler-Adams
  • Karin Kast
  • Laurence Venat-Bouvet
  • Dominique Stoppa-Lyonnet
  • Georgia Chenevix-Trench
  • Douglas F. Easton
  • Robert J. Klein
  • Mark J. Daly
  • Eitan Friedman
  • Michael Dean
  • Andrew G. Clark
  • David M. Altshuler
  • Antonis C. Antoniou
  • Fergus J. Couch
  • Kenneth Offit
  • Bert Gold
Original Investigation

Abstract

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

Keywords

Linkage Disequilibrium Block Haplotype Structure Ashkenazi Jewish Extended Haplotype Ashkenazi Jewish Population 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AJ

Ashkenazi Jews

CIMBA

Consortium of Investigators of Modifiers of BRCA1 and BRCA2

CNJ

Caucasian non-Jews

LD

Linkage disequilibrium

MAF

Minor allele frequency

MJ

Median joining

PCA

Principal components analysis

SNP

Single nucleotide polymorphism

IBD

Identity by descent

Notes

Acknowledgments

This work was supported in part by federal funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also acknowledge the support of the Starr Foundation, the Breast Cancer Research Foundation and the Sabin Family Fund. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the US government. The authors wish to thank Dr. Colm O’hUigin, who provided valuable comments on an early version of this manuscript.

UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye and Patricia Harrington for their contributions toward the UKFOCR.

The GEMO study (Cancer Genetics Network “Groupe Génétique et Cancer”, Fédération Nationale des Centres de Lutte Contre le Cancer, France) is supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association “Le cancer du sein, parlons-en!” Award.

We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, & UMR5201 CNRS, Université de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, François Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Centre René Huguenin, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Cécile Cassini, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. Creighton University, Omaha, USA: Henry T. Lynch.

For kConFab, we wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinic and the Clinical Follow Up Study (funded 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.

The CONSIT TEAM study (Consorzio degli Studi Italiani Tumori Ereditari Alla Mammella), acknowledges Marco Pierotti, Siranoush Manoukian, Daniela Zaffaroni, Carla B. Ripamonti and Paolo Radice of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy and Loris Bernard of the Cogentech, Consortium for Genomic Technologies, Milan, Italy. We thank all patients and families who participated in this study. This study was supported by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1,000’).

For the Mayo Study, the authors would like to acknowledge funding from the Breast Cancer Research Foundation, Komen Foundation, and NIHCA116167.

The Cancer Prevention Institute of California was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registry (CFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the CFR.

The SWE-BRCA study acknowledge the study collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. The HCSC study was supported by RD06/0020/0021 from ISCIII.

The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Collaborating Centers are Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hogervorst, S. Verhoef, M. Verheus, L.J. van ‘t Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collée, A.M.W. van den Ouweland, A. Jager, M.J. Hooning, M.M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M.P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E.B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756.

The Ohio State University Clinical Cancer Genetics (OSU CCG) study is supported by the OSU Comprehensive Cancer Center. We thank Leigha Senter and Kevin Sweet for patient accrual, sample ascertainment and database management. The Human Genetics Sample bank processed the samples.

This work was supported by Cancer Care Ontario and the US National Cancer Institute, National Institutes of Health under RFA # CA- 06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the BCFR. We wish to thank Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.

Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE).

Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins, Kashmir Randhawa. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell, Nafisa Patel. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385.

CBCS: We thank Bent Ejlertsen, Mette K. Andersen, Anne-Marie Gerdes and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE foundation for financial support.

Conflict of interest

The authors report no conflicts of interest.

Supplementary material

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Supplementary material 3 (EPS 2386 kb)
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Supplementary material 4 (DOCX 14 kb)

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Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Kate M. Im
    • 1
  • Tomas Kirchhoff
    • 2
  • Xianshu Wang
    • 3
  • Todd Green
    • 4
    • 5
    • 6
  • Clement Y. Chow
    • 7
  • Joseph Vijai
    • 2
  • Joshua Korn
    • 4
    • 5
    • 6
  • Mia M. Gaudet
    • 8
  • Zachary Fredericksen
    • 3
  • V. Shane Pankratz
    • 3
  • Candace Guiducci
    • 4
    • 5
    • 6
  • Andrew Crenshaw
    • 4
    • 5
    • 6
  • Lesley McGuffog
    • 9
  • Christiana Kartsonaki
    • 9
  • Jonathan Morrison
    • 9
  • Sue Healey
    • 10
  • Olga M. Sinilnikova
    • 11
    • 12
  • Phuong L. Mai
    • 13
  • Mark H. Greene
    • 13
  • Marion Piedmonte
    • 14
  • Wendy S. Rubinstein
    • 15
  • HEBON
    • 16
  • Frans B. Hogervorst
    • 16
  • Matti A. Rookus
    • 17
  • J. Margriet Collée
    • 18
  • Nicoline Hoogerbrugge
    • 19
  • Christi J. van Asperen
    • 20
  • Hanne E. J. Meijers-Heijboer
    • 21
  • Cees E. Van Roozendaal
    • 22
  • Trinidad Caldes
    • 23
  • Pedro Perez-Segura
    • 23
  • Anna Jakubowska
    • 24
  • Jan Lubinski
    • 24
  • Tomasz Huzarski
    • 24
  • Paweł Blecharz
    • 25
  • Heli Nevanlinna
    • 26
  • Kristiina Aittomäki
    • 27
  • Conxi Lazaro
    • 28
  • Ignacio Blanco
    • 28
  • Rosa B. Barkardottir
    • 29
    • 30
  • Marco Montagna
    • 31
  • Emma D’Andrea
    • 31
    • 32
  • kConFab
    • 33
  • Peter Devilee
    • 34
  • Olufunmilayo I. Olopade
    • 35
  • Susan L. Neuhausen
    • 36
  • Bernard Peissel
    • 37
  • Bernardo Bonanni
    • 38
  • Paolo Peterlongo
    • 39
    • 40
  • Christian F. Singer
    • 41
    • 42
  • Gad Rennert
    • 43
  • Flavio Lejbkowicz
    • 43
  • Irene L. Andrulis
    • 44
    • 45
    • 46
    • 47
  • Gord Glendon
    • 45
  • Hilmi Ozcelik
    • 44
    • 45
    • 46
  • Ontario Cancer Genetics Network
    • 45
  • Amanda Ewart Toland
    • 48
  • Maria Adelaide Caligo
    • 49
  • SWE-BRCA
    • 50
  • Mary S. Beattie
    • 51
  • Salina Chan
    • 52
  • UKFOCR
    • 53
  • Susan M. Domchek
    • 54
  • Katherine L. Nathanson
    • 54
  • Timothy R. Rebbeck
    • 54
  • Catherine Phelan
    • 55
  • Steven Narod
    • 56
  • Esther M. John
    • 57
  • John L. Hopper
    • 58
  • Saundra S. Buys
    • 59
  • Mary B. Daly
    • 60
  • Melissa C. Southey
    • 61
  • Mary-Beth Terry
    • 62
  • Nadine Tung
    • 63
  • Thomas v. O. Hansen
    • 64
  • Ana Osorio
    • 65
    • 66
  • Javier Benitez
    • 66
    • 67
  • Mercedes Durán
    • 68
  • Jeffrey N. Weitzel
    • 69
  • Judy Garber
    • 70
  • Ute Hamann
    • 71
  • EMBRACE
    • 9
  • Susan Peock
    • 9
  • Margaret Cook
    • 9
  • Clare T. Oliver
    • 9
  • Debra Frost
    • 9
  • Radka Platte
    • 9
  • D. Gareth Evans
    • 72
  • Ros Eeles
    • 73
  • Louise Izatt
    • 74
  • Joan Paterson
    • 75
  • Carole Brewer
    • 76
  • Shirley Hodgson
    • 77
  • Patrick J. Morrison
    • 78
  • Mary Porteous
    • 79
  • Lisa Walker
    • 80
  • Mark T. Rogers
    • 81
  • Lucy E. Side
    • 82
  • Andrew K. Godwin
    • 83
  • Rita K. Schmutzler
    • 84
  • Barbara Wappenschmidt
    • 84
  • Yael Laitman
    • 87
  • Alfons Meindl
    • 88
  • Helmut Deissler
    • 89
  • Raymonda Varon-Mateeva
    • 90
  • Sabine Preisler-Adams
    • 91
  • Karin Kast
    • 92
  • Laurence Venat-Bouvet
    • 85
  • Dominique Stoppa-Lyonnet
    • 86
  • Georgia Chenevix-Trench
    • 10
  • Douglas F. Easton
    • 9
  • Robert J. Klein
    • 2
  • Mark J. Daly
    • 4
    • 5
    • 6
  • Eitan Friedman
    • 87
  • Michael Dean
    • 1
  • Andrew G. Clark
    • 7
  • David M. Altshuler
    • 4
    • 5
    • 6
  • Antonis C. Antoniou
    • 9
  • Fergus J. Couch
    • 3
  • Kenneth Offit
    • 2
  • Bert Gold
    • 1
    • 93
  1. 1.Center for Cancer Research, Cancer Inflammation Program, Human Genetics SectionNational Cancer InstituteFrederickUSA
  2. 2.Clinical Genetics Service, Department of Medicine, Program in Cancer Prevention and Population Research, Program in Cancer Biology and Genetics (RJK)Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  4. 4.Department of Genetics and of MedicineHarvard Medical SchoolBostonUSA
  5. 5.Program in Medical and Population GeneticsBroad Institute of Harvard University and MITCambridgeUSA
  6. 6.Department of Molecular Biology, Center for Human Genetic ResearchMassachusetts General HospitalBostonUSA
  7. 7.Department of Molecular Biology and GeneticsCornell UniversityIthacaUSA
  8. 8.Epidemiology Research ProgramAmerican Cancer SocietyAtlantaUSA
  9. 9.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
  10. 10.Genetics and Population Health DivisionQueensland Institute of Medical ResearchBrisbaneAustralia
  11. 11.Unité Mixte de Génétique Constitutionnelle des Cancers FréquentsCentre Hospitalier Universitaire de Lyon/Centre Léon BérardLyonFrance
  12. 12.Centre Léon BérardUniversité de LyonLyonFrance
  13. 13.Clinical Genetics BranchNational Cancer InstituteRockvilleUSA
  14. 14.GOG Statistical and Data CenterRoswell Park Cancer InstituteBuffaloUSA
  15. 15.NorthShore University Health SystemEvanstonUSA
  16. 16.Family Cancer ClinicNetherlands Cancer InstituteAmsterdamThe Netherlands
  17. 17.Department of EpidemiologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  18. 18.Department of Clinical Genetics, Family Cancer ClinicErasmus University Medical CenterRotterdamThe Netherlands
  19. 19.Hereditary Cancer ClinicRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  20. 20.Department of Clinical GeneticsLeiden University Medical CenterLeidenThe Netherlands
  21. 21.Department of Clinical GeneticsVU Medical CenterAmsterdamThe Netherlands
  22. 22.Department of Clinical GeneticsUniversity Medical CenterMaastrichtThe Netherlands
  23. 23.Molecular Oncology LaboratoryHospital Clinico San CarlosMadridSpain
  24. 24.International Hereditary Cancer Center, Department of Genetics and PathologyPomeranian Medical UniversitySzczecinPoland
  25. 25.Center of OncologyMaria Sklodowska-Curie Memorial InstituteKrakówPoland
  26. 26.Department of Obstetrics and GynecologyHelsinki University Central HospitalHelsinkiFinland
  27. 27.Department of Clinical GeneticsHelsinki University Central HospitalHelsinkiFinland
  28. 28.Hereditary Cancer ProgramCatalan Institute of Oncology-IDIBELLBarcelonaSpain
  29. 29.Department of PathologyLandspitali–LSHReykjavikIceland
  30. 30.Faculty of MedicineUniversity of IcelandReykjavikIceland
  31. 31.Immunology and Molecular Oncology UnitIstituto Oncologico Veneto IOV, IRCCSPaduaItaly
  32. 32.Department of Oncology and Surgical SciencesUniversity of PaduaPaduaItaly
  33. 33.Kathleen Cuningham Foundation Consortium for Research into Familial Breast CancerPeter MacCallum Cancer CentreMelbourneAustralia
  34. 34.Department of Human Genetics and PathologyLeiden University Medical CenterLeidenThe Netherlands
  35. 35.Center for Clinical Cancer Genetics and Global Health, Department of MedicineUniversity of Chicago Medical CenterChicagoUSA
  36. 36.Department of Population SciencesThe Beckman Research Institute of the City of HopeDuarteUSA
  37. 37.Unit of Medical Genetics, Department of Preventive and Predictive MedicineFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanItaly
  38. 38.Division of Cancer Prevention and GeneticsIstituto Europeo di Oncologia (IEO)MilanItaly
  39. 39.Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale Tumori (INT)MilanItaly
  40. 40.IFOMFondazione Istituto FIRC di Oncologia MolecolareMilanItaly
  41. 41.Department of Obstetrics and GynecologyUniversity of ViennaViennaAustria
  42. 42.Comprehensive Cancer Medical CenterUniversity of ViennaViennaAustria
  43. 43.CHS National Cancer Control Center and Department of Community Medicine and EpidemiologyCarmel Medical Center and Technion Faculty of MedicineHaifaIsrael
  44. 44.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  45. 45.Cancer Care OntarioUniversity of TorontoTorontoCanada
  46. 46.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  47. 47.Department of Molecular GeneticsUniversity of TorontoTorontoCanada
  48. 48.Department of Molecular Virology Immunology, and Medical Genetics and Internal MedicineThe Ohio State UniversityColumbusUSA
  49. 49.Section of Genetic Oncology, Department of Laboratory MedicineUniversity of Pisa and Santa Chiara University HospitalPisaItaly
  50. 50.Department of OncologyLund UniversityLundSweden
  51. 51.Division of General Internal Medicine, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA
  52. 52.Cancer Risk ProgramUniversity of California San Francisco, Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA
  53. 53.Department of OncologyUniversity of CambridgeCambridgeUK
  54. 54.Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA
  55. 55.Moffitt Cancer CenterTampaUSA
  56. 56.Women’s College Research InstituteTorontoCanada
  57. 57.Cancer Prevention Institute of CaliforniaFremontUSA
  58. 58.Centre for Genetic EpidemiologyUniversity of MelbourneVictoriaAustralia
  59. 59.Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  60. 60.Fox Chase Cancer CenterPhiladelphiaUSA
  61. 61.Department of PathologyThe University of MelbourneVictoriaAustralia
  62. 62.Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  63. 63.Division of Hematology-OncologyBeth Israel Deaconess Medical CenterBostonUSA
  64. 64.Genomic Medicine, Department of Clinical Biochemistry, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  65. 65.Human Genetics Group, Human Cancer Genetics ProgrammeSpanish National Cancer Research CentreMadridSpain
  66. 66.Spanish Network on Rare Diseases (CIBERER)MadridSpain
  67. 67.Human Genetics Group and Genotyping Unit, Human Cancer Genetics ProgrammeSpanish National Cancer Research CentreMadridSpain
  68. 68.Institute of Biology and Molecular GeneticsUniversidad de Valladolid (IBGM-UVA)ValladolidSpain
  69. 69.Division of Clinical Cancer GeneticsCity of Hope Cancer CenterDuarteUSA
  70. 70.Dana Farber Cancer InstituteHarvard UniversityBostonUSA
  71. 71.Molecular Genetics of Breast CancerDeutsches Krebsforschungszentrum (DKFZ)HeidelbergGermany
  72. 72.Genetic Medicine, Manchester Academic Health Sciences CentreCentral Manchester University Hospitals NHS Foundation TrustManchesterUK
  73. 73.Oncogenetics TeamThe Institute of Cancer Research and Royal Marsden NHS Foundation TrustSurreyUK
  74. 74.Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation TrustLondonUK
  75. 75.Department of Clinical Genetics, East Anglian Regional Genetics ServiceAddenbrookes HospitalCambridgeUK
  76. 76.Department of Clinical GeneticsRoyal Devon & Exeter HospitalExeterUK
  77. 77.Clinical Genetics Department, St Georges HospitalUniversity of LondonLondonUK
  78. 78.Northern Ireland Regional Genetics CentreBelfast City HospitalBelfastUK
  79. 79.South East of Scotland Regional Genetics ServiceWestern General HospitalEdinburghUK
  80. 80.Oxford Regional Genetics ServiceChurchill HospitalOxfordUK
  81. 81.All Wales Medical Genetics ServicesUniversity Hospital of WalesCardiffUK
  82. 82.North East Thames Regional Genetics ServiceGreat Ormond Street Hospital for Children NHS TrustLondonUK
  83. 83.Department of Pathology and LaboratoryUniversity of Kansas Medical CenterKansas CityUSA
  84. 84.University Hospital of CologneCologneGermany
  85. 85.Department of Medical OncologyCentre Hospitalier Universitaire DupuytrenLimogesFrance
  86. 86.INSERM U509, Service de Génétique Oncologique, Institut CurieUniversité Paris-DescartesParisFrance
  87. 87.The Susan Levy Gertner Oncogenetics unit, Institute of GeneticsSheba Medical CenterTel HashomerIsrael
  88. 88.Technical University MunichMunichGermany
  89. 89.University Hospital UlmUlmGermany
  90. 90.Institute of Human GeneticsCharite Campus Virchow KlinikumBerlinGermany
  91. 91.Institute of Human GeneticsUniversity of MünsterMünsterGermany
  92. 92.Department of Gynaecology and ObstetricsUniversity Hospital Carl Gustav, Technical University DresdenDresdenGermany
  93. 93.NCI-FrederickFrederickUSA

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