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Oncotarget. 2017 Oct 12;8(61):102769-102782. doi: 10.18632/oncotarget.21800. eCollection 2017 Nov 28.

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

Jiao X1, Aravidis C1,2, Marikkannu R1, Rantala J1, Picelli S1, Adamovic T1, Liu T1, Maguire P1, Kremeyer B1, Luo L1, von Holst S1, Kontham V1, Thutkawkorapin J1, Margolin S3, Du Q1, Lundin J1, Michailidou K4,5, Bolla MK4, Wang Q4, Dennis J4, Lush M4, Ambrosone CB6, Andrulis IL7,8, Anton-Culver H9, Antonenkova NN10, Arndt V11, Beckmann MW12, Blomqvist C13, Blot W14,15, Boeckx B16,17, Bojesen SE18,19,20, Bonanni B21, Brand JS22, Brauch H23,24,25, Brenner H11,25,26, Broeks A27, Brüning T28, Burwinkel B29,30, Cai Q14, Chang-Claude J31,32; NBCS Collaborators, Couch FJ33, Cox A34, Cross SS35, Deming-Halverson SL14, Devilee P36,37, Dos-Santos-Silva I38, Dörk T39, Eriksson M22, Fasching PA12,40, Figueroa J41,42, Flesch-Janys D43,44, Flyger H45, Gabrielson M22, García-Closas M42, Giles GG46,47, González-Neira A48, Guénel P49, Guo Q50, Gündert M29,30, Haiman CA51, Hallberg E52, Hamann U53, Harrington P54, Hooning MJ55, Hopper JL47, Huang G53, Jakubowska A56, Jones ME57, Kerin MJ58, Kosma VM59,60,61, Kristensen VN62,63,64, Lambrechts D16,17, Le Marchand L65, Lubinski J56, Mannermaa A59,60,61, Martens JWM55, Meindl A66, Milne RL46,47, Mulligan AM67,68, Neuhausen SL69, Nevanlinna H70, Peto J38, Pylkäs K71,72, Radice P73, Rhenius V54, Sawyer EJ74, Schmidt MK27,75, Schmutzler RK76,77,78, Seynaeve C55, Shah M54, Simard J79, Southey MC80, Swerdlow AJ57,81, Truong T49, Wendt C3, Winqvist R71,72, Zheng W14; kConFab/AOCS Investigators, Benitez J48,82, Dunning AM54, Pharoah PDP4,54, Easton DF4,54, Czene K22, Hall P22, Lindblom A1.

Author information

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 Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
34
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
35
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
36
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
37
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
38
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
39
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
40
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
41
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
42
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
43
Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
44
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
45
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
46
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
47
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia.
48
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
49
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
50
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
51
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
52
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
53
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
54
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
55
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
56
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
57
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
58
School of Medicine, National University of Ireland, Galway, Ireland.
59
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
60
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
61
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
62
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
63
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
64
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
65
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
66
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
67
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
68
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
69
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
70
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
71
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
72
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
73
Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
74
Research Oncology, Guy's Hospital, King's College London, London, UK.
75
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
76
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
77
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
78
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
79
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada.
80
Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
81
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
82
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.

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.

KEYWORDS:

familial breast cancer; linkage analysis; risk haplotype; sequencing

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