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Oncotarget. 2016 Dec 6;7(49):80140-80163. doi: 10.18632/oncotarget.12818.

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Author information

1
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada.
2
Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France.
3
Centre National de la Recherche Scientifique, Toulouse, France.
4
Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
5
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
6
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
7
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
8
Centre de Recherche du CHU de Québec - Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Université Laval, Quebec, Canada.
9
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
10
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
11
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
12
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
13
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
14
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
15
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
16
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
17
Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
18
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
19
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
20
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
21
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
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, German Cancer Research Center, Heidelberg, Germany.
26
Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
27
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
28
Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
29
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
30
University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
31
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
32
Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
33
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
34
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
35
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
36
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
37
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
38
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
39
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
40
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
41
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
42
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
43
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
44
Department of Medicine, McGill University, Montreal, Canada.
45
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
46
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
47
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, VilleJuif, France.
48
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
49
Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
50
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
51
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
52
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
53
Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK.
54
Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
55
Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland.
56
Vesalius Research Center, Leuven, Belgium.
57
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
58
University of Hawaii Cancer Center, Honolulu, HI, USA.
59
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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 Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
63
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
64
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
65
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
66
Multidisciplinary Breast Center, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
67
Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
68
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
69
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
70
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere, Scientifico, Istituto Nazionale Tumori, Milan, Italy.
71
Research Oncology, Guy's Hospital, King's College London, London, UK.
72
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
73
Department of Pathology, The University of Melbourne, Melbourne, Australia.
74
Division of Genetics and Epidemiology & Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
75
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
76
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
77
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
78
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
79
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
80
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
81
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
82
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.

Abstract

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

KEYWORDS:

association studies; breast cancer; cis-regulatory variants; differential allelic expression; genetic susceptibility

PMID:
27792995
PMCID:
PMC5340257
DOI:
10.18632/oncotarget.12818
[Indexed for MEDLINE]
Free PMC Article

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