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Priority Research Papers:

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Xiang Jiao _, Christos Aravidis, Rajeshwari Marikkannu, Johanna Rantala, Simone Picelli, Tatjana Adamovic, Tao Liu, Paula Maguire, Barbara Kremeyer, Liping Luo, Susanna von Holst, Vinaykumar Kontham, Jessada Thutkawkorapin, Sara Margolin, Quan Du, Johanna Lundin, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Christine B. Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Matthias W. Beckmann, Carl Blomqvist, William Blot, Bram Boeckx, Stig E. Bojesen, Bernardo Bonanni, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Qiuyin Cai, Jenny Chang-Claude, NBCS Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Sandra L. Deming-Halverson, Peter Devilee, Isabel dos-Santos-Silva, Thilo Dörk, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Montserrat García-Closas, Graham G. Giles, Anna González-Neira, Pascal Guénel, Qi Guo, Melanie Gündert, Christopher A. Haiman, Emily Hallberg, Ute Hamann, Patricia Harrington, Maartje J. Hooning, John L. Hopper, Guanmengqian Huang, Anna Jakubowska, Michael E. Jones, Michael J. Kerin, Veli-Matti Kosma, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Jan Lubinski, Arto Mannermaa, John W.M. Martens, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Julian Peto, Katri Pylkas, Paolo Radice, Valerie Rhenius, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Caroline Seynaeve, Mitul Shah, Jacques Simard, Melissa C. Southey, Anthony J. Swerdlow, Therese Truong, Camilla Wendt, Robert Winqvist, Wei Zheng, kConFab/AOCS Investigators, Javier Benitez, Alison M. Dunning, Paul D.P. Pharoah, Douglas F. Easton, Kamila Czene, Per Hall and Annika Lindblom

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Oncotarget. 2017; 8:102769-102782. https://doi.org/10.18632/oncotarget.21800

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Abstract

Xiang Jiao1, Christos Aravidis1,2, Rajeshwari Marikkannu1, Johanna Rantala1, Simone Picelli1, Tatjana Adamovic1, Tao Liu1, Paula Maguire1, Barbara Kremeyer1, Liping Luo1, Susanna von Holst1, Vinaykumar Kontham1, Jessada Thutkawkorapin1, Sara Margolin3, Quan Du1, Johanna Lundin1, Kyriaki Michailidou4,5, Manjeet K. Bolla4, Qin Wang4, Joe Dennis4, Michael Lush4, Christine B. Ambrosone6, Irene L. Andrulis7,8, Hoda Anton-Culver9, Natalia N. Antonenkova10, Volker Arndt11, Matthias W. Beckmann12, Carl Blomqvist13, William Blot14,15, Bram Boeckx16,17, Stig E. Bojesen18,19,20, Bernardo Bonanni21, Judith S. Brand22, Hiltrud Brauch23,24,25, Hermann Brenner11,25,26, Annegien Broeks27, Thomas Brüning28, Barbara Burwinkel29,30, Qiuyin Cai14, Jenny Chang-Claude31,32, NBCS Collaborators33,34,35,36,37,38,39,40,41,42,43,44,45,46,47, Fergus J. Couch48, Angela Cox49, Simon S. Cross50, Sandra L. Deming-Halverson14, Peter Devilee51,52, Isabel dos-Santos-Silva53, Thilo Dörk54, Mikael Eriksson22, Peter A. Fasching12,55, Jonine Figueroa56,57, Dieter Flesch-Janys58,59, Henrik Flyger60, Marike Gabrielson22, Montserrat García-Closas57, Graham G. Giles61,62, Anna González-Neira63, Pascal Guénel64, Qi Guo65, Melanie Gündert29,30, Christopher A. Haiman66, Emily Hallberg67, Ute Hamann68, Patricia Harrington69, Maartje J. Hooning70, John L. Hopper62, Guanmengqian Huang68, Anna Jakubowska71, Michael E. Jones72, Michael J. Kerin73, Veli-Matti Kosma74,75,76, Vessela N. Kristensen37,41,42, Diether Lambrechts16,17, Loic Le Marchand77, Jan Lubinski71, Arto Mannermaa74,75,76, John W.M. Martens70, Alfons Meindl78, Roger L. Milne61,62, Anna Marie Mulligan79,80, Susan L. Neuhausen81, Heli Nevanlinna82, Julian Peto53, Katri Pylkäs83,84, Paolo Radice85, Valerie Rhenius69, Elinor J. Sawyer86, Marjanka K. Schmidt27,87, Rita K. Schmutzler88,89,90, Caroline Seynaeve70, Mitul Shah69, Jacques Simard91, Melissa C. Southey92, Anthony J. Swerdlow72,93, Thérèse Truong64, Camilla Wendt3, Robert Winqvist83,84, Wei Zheng14, kConFab/AOCS Investigators 94,95, Javier Benitez63,96, Alison M. Dunning69, Paul D.P. Pharoah4,69, Douglas F. Easton4,69, Kamila Czene22, Per Hall22 and Annika Lindblom1

1 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

2 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

3 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden

4 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

5 Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6 Roswell Park Cancer Institute, Buffalo, NY, USA

7 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada

8 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

9 Department of Epidemiology, University of California Irvine, Irvine, CA, USA

10 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus

11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

12 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

13 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

14 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

15 International Epidemiology Institute, Rockville, MD, USA

16 VIB Center for Cancer Biology, VIB, Leuven, Belgium

17 Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium

18 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

19 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

20 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

21 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy

22 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

23 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

24 University of Tübingen, Tübingen, Germany

25 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

26 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany

27 Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

28 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany

29 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany

30 Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany

31 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

32 Research Group Genetic Cancer Epidemiology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

33 Department of Oncology, Haukeland University Hospital, Bergen, Norway

34 Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway

35 Department of Pathology, Akershus University Hospital, Lørenskog, Norway

36 Department of Breast-Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway

37 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway

38 Department of Breast and Endocrine Surgery, Oslo University Hospital, Ullevål, Oslo, Norway

39 Department of Research, Vestre Viken Hospital, Drammen, Norway

40 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway

41 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

42 Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway

43 National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital Radiumhospitalet, Oslo, Norway

44 Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway

45 Department of Radiology and Nuclear Medicine, Oslo University Hospital Radiumhospitalet, Oslo, Norway

46 Oslo University Hospital, Oslo, Norway

47 Department of Oncology, Oslo University Hospital Ullevål, Oslo, Norway

48 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

49 Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

50 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK

51 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

52 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

53 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

54 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany

55 David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA

56 Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK

57 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA

58 Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

59 Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

60 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

61 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia

62 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia

63 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain

64 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France

65 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

66 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

67 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

68 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

69 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK

70 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

71 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

72 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

73 School of Medicine, National University of Ireland, Galway, Ireland

74 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland

75 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

76 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

77 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

78 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany

79 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

80 Laboratory Medicine Program, University Health Network, Toronto, ON, Canada

81 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

82 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

83 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland

84 Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland

85 Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy

86 Research Oncology, Guy’s Hospital, King’s College London, London, UK

87 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands

88 Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany

89 Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany

90 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

91 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada

92 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia

93 Division of Breast Cancer Research, The Institute of Cancer Research, London, UK

94 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia

95 The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Australia

96 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain

Correspondence to:

Annika Lindblom, email:

Keywords: familial breast cancer, linkage analysis, risk haplotype, sequencing

Received: July 06, 2017 Accepted: August 31, 2017 Published: October 12, 2017

Abstract

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.


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