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Breast Cancer Res Treat. 2017 Jan;161(1):117-134. doi: 10.1007/s10549-016-4018-2. Epub 2016 Oct 28.

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

Hamdi Y1, Soucy P1, Kuchenbaeker KB2,3, Pastinen T4,5, Droit A1, Lemaçon A1, Adlard J6, Aittomäki K7, Andrulis IL8,9, Arason A10,11, Arnold N12, Arun BK13, Azzollini J14, Bane A15, Barjhoux L16, Barrowdale D2, Benitez J17,18,19, Berthet P20, Blok MJ21, Bobolis K22, Bonadona V23, Bonanni B24, Bradbury AR25, Brewer C26, Buecher B27, Buys SS28, Caligo MA29, Chiquette J30, Chung WK31, Claes KB32, Daly MB33, Damiola F16, Davidson R34, De la Hoya M35, De Leeneer K32, Diez O36, Ding YC37, Dolcetti R38,39, Domchek SM25, Dorfling CM40, Eccles D41, Eeles R42, Einbeigi Z43, Ejlertsen B44; EMBRACE, Engel C45,46, Gareth Evans D47, Feliubadalo L48, Foretova L49, Fostira F50, Foulkes WD51, Fountzilas G52, Friedman E53,54, Frost D2, Ganschow P55, Ganz PA56, Garber J57, Gayther SA58; GEMO Study Collaborators, Gerdes AM59, Glendon G8, Godwin AK60, Goldgar DE61, Greene MH62, Gronwald J63, Hahnen E64, Hamann U65, Hansen TV66, Hart S67, Hays JL68,69,70; HEBON, Hogervorst FB71, Hulick PJ72, Imyanitov EN73, Isaacs C74, Izatt L75, Jakubowska A63, James P76,77, Janavicius R78,79, Jensen UB80, John EM81,82, Joseph V83, Just W84, Kaczmarek K63, Karlan BY85; KConFab Investigators, Kets CM86, Kirk J87, Kriege M88, Laitman Y53, Laurent M27, Lazaro C48, Leslie G2, Lester J85, Lesueur F89, Liljegren A90, Loman N91, Loud JT62, Manoukian S14, Mariani M14, Mazoyer S92, McGuffog L2, Meijers-Heijboer HE93, Meindl A12, Miller A94, Montagna M95, Mulligan AM9,96, Nathanson KL25, Neuhausen SL37, Nevanlinna H97, Nussbaum RL98, Olah E99, Olopade OI100, Ong KR101, Oosterwijk JC102, Osorio A17,18, Papi L103, Park SK104, Pedersen IS105, Peissel B14, Segura PP106, Peterlongo P107, Phelan CM108, Radice P109, Rantala J110, Rappaport-Fuerhauser C111, Rennert G112, Richardson A113, Robson M114, Rodriguez GC115, Rookus MA116, Schmutzler RK64,117,118, Sevenet N119, Shah PD25, Singer CF111, Slavin TP55, Snape K120, Sokolowska J121, Sønderstrup IM122, Southey M123, Spurdle AB124, Stadler Z125, Stoppa-Lyonnet D27, Sukiennicki G63, Sutter C126, Tan Y111, Tea MK111, Teixeira MR127,128, Teulé A129, Teo SH130,131, Terry MB132, Thomassen M133, Tihomirova L134, Tischkowitz M51,135, Tognazzo S95, Toland AE136, Tung N137, van den Ouweland AM138, van der Luijt RB139, van Engelen K140, van Rensburg EJ40, Varon-Mateeva R141, Wappenschmidt B64, Wijnen JT142, Rebbeck T25,143, Chenevix-Trench G124, Offit K83, Couch FJ67,144, Nord S145, Easton DF2, Antoniou AC2, Simard J146.

Author information

1
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada.
2
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
3
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus Hinxton, Cambridge, CB10 1HH, UK.
4
Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada.
5
McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada.
6
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
7
Department of Clinical Genetics, Helsinki University Hospital, HUS, Meilahdentie 2, P.O. BOX 160, 00029, Helsinki, Finland.
8
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
9
Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
10
Department of Pathology hus 9, Landspitali-LSH v/Hringbraut, 101, Reykjavík, Iceland.
11
BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavík, Iceland.
12
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, 24105, Kiel, Germany.
13
Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, 1515 Pressler Street CBP 5, Houston, TX, 77030, USA.
14
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy.
15
Department of Pathology & Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, 711 Concession Street, Hamilton, ON, L8V 1C3, Canada.
16
Bâtiment Cheney D, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon, France.
17
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
18
Biomedical Network on Rare Diseases (CIBERER), 28029, Madrid, Spain.
19
Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
20
Centre François Baclesse, 3 avenue Général Harris, 14076, Caen, France.
21
Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
22
City of Hope Clinical Cancer Genomics Community Research Network, 1500 East Duarte Road, Duarte, CA, 91010, USA.
23
Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon, France.
24
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141, Milan, Italy.
25
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
26
Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, EX1 2ED, UK.
27
Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
28
Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
29
Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
30
Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Quebec, QC, G1S 4L8, Canada.
31
Departments of Pediatrics and Medicine, Columbia University, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
32
Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
33
Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
34
Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, G51 4TF, UK.
35
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
36
Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Clinical and Molecular Genetics Area, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
37
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
38
Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) National Cancer Institute, Via Franco Gallini 2, 33081, Aviano, PN, Italy.
39
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
40
Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007, South Africa.
41
Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, Southampton, UK.
42
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, SM2 5NG, UK.
43
Department of Oncology, Sahlgrenska University Hospital, 41345, Göteborg, Sweden.
44
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
45
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
46
LIFE, Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
47
Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, M13 9WL, UK.
48
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, L'Hospitalet, 08908, Barcelona, Spain.
49
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
50
Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos", Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi Attikis, Athens, Greece.
51
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada.
52
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloníki, Greece.
53
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Ramat Gan, Israel.
54
Sackler Faculty of Medicine, Tel Aviv University, 69978, Ramat Aviv, Israel.
55
Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
56
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA, 90095-6900, USA.
57
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
58
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
59
Department of Clincial Genetics, Rigshospitalet, Blegdamsvej 9, 4062, Copenhagen, Denmark.
60
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040, Kansas City, Kansas, USA.
61
Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT, 84132, USA.
62
Clinical Genetics Branch, DCEG, NCI NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA.
63
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland.
64
Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931, Cologne, Germany.
65
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
66
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
67
Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
68
Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA.
69
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH, 43210, USA.
70
Comprehensive Cancer Center Arthur C. James Cancer Hospital and Richard J. Solove Research Institute Biomedical Research Tower, Room 588, 460 West 12th Avenue, Columbus, OH, 43210, USA.
71
Family Cancer Clinic, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands.
72
Center for Medical Genetics, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, 1000 Central Street, Suite 620, Evanston, IL, 60201, USA.
73
N.N. Petrov Institute of Oncology, St. Petersburg, Russia, 197758.
74
Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, 20007, USA.
75
Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
76
Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
77
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, 3010, Australia.
78
Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Santariskiu st. 2, 08661, Vilnius, Lithuania.
79
State Research Institute Centre for Innovative Medicine, Zygymantu st. 9, Vilnius, Lithuania.
80
Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21C, Århus N, Denmark.
81
Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue Suite 300, Fremont, CA, 94538, USA.
82
Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
83
Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
84
Institute of Human Genetics, University of Ulm, 89091, Ulm, Germany.
85
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, 90048, USA.
86
Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
87
Westmead Hospital, Familial Cancer Service, Hawkebury Road, P.O. Box 533, Wentworthville, NSW, 2145, Australia.
88
Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, P.O. Box 5201, 3008 AE, Rotterdam, The Netherlands.
89
Genetic Epidemiology of Cancer Team, INSERM U900, Institut Curie Mines ParisTech, PSL University, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
90
Department of Oncology, Karolinska University Hospital, 17176, Stockholm, Sweden.
91
Department of Oncology, Lund University Hospital, 22185, Lund, Sweden.
92
Lyon Neuroscience Research Center-CRNL, INSERM U1028, CNRS UMR5292, University of Lyon, Lyon, France.
93
Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
94
NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY, 14263, USA.
95
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
96
Department of Laboratory Medicine and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada.
97
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Haartmaninkatu 8, HUS, P.O. BOX 700, 00029, Helsinki, Finland.
98
Department of Medicine and Genetics, University of California, 513 Parnassus Ave., HSE 901E, San Francisco, CA, 94143-0794, USA.
99
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
100
Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA.
101
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK.
102
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
103
Unit of Medical Genetics, Department of Biomedical Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
104
Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
105
Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Reberbansgade 15, Ålborg, Denmark.
106
Department of Oncology, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
107
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO Campus, Via Adamello 16, 20139, Milan, Italy.
108
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
109
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab via GA Amadeo 42, 20133, Milan, Italy.
110
Department of Clinical Genetics, Karolinska University Hospital, L5:03, 171 76, Stockholm, Sweden.
111
Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A, 1090, Vienna, Austria.
112
Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, 7 Michal St., 34362, Haifa, Israel.
113
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
114
Clinical Genetics, Services Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
115
Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, 2650 Ridge Avenue, Suite 1507, Walgreens, Evanston, IL, 60201, USA.
116
Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands.
117
Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, 50931, Cologne, Germany.
118
Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
119
Oncogénétique, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux, France.
120
Medical Genetics Unit, St George's, University of London, London, SW17 0RE, UK.
121
Laboratoire de génétique médicale Nancy Université, Centre Hospitalier Régional et Universitaire, Rue du Morvan cedex 1, 54511, Vandoeuvre-les-Nancy, France.
122
Department of Pathology Region Zealand Section Slagelse, Slagelse Hospital, Ingemannsvej 18 Slagelse, Cpoenhagen, Denmark.
123
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, 3010, Australia.
124
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.
125
Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
126
Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
127
Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
128
Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
129
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, L'Hospitalet, 08908, Barcelona, Spain.
130
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Malaysia.
131
University Malaya Cancer Research Institute, University Malaya, 1 Jalan SS12/1A, 50603, Kuala Lumpur, Malaysia.
132
Department of Epidemiology, Columbia University, New York, NY, USA.
133
Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
134
Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia.
135
Department of Medical Genetics Level 6 Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Box 134, Cambridge, CB2 0QQ, UK.
136
Division of Human Genetics, Departments of Internal Medicine and Cancer Biology and Genetics Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH, 43210, USA.
137
Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA.
138
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, 330 Brookline Avenue, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
139
Department of Medical Genetics, University Medical Center Utrecht, 3584 EA, Utrecht, The Netherlands.
140
Department of Clinical Genetics, Academic Medical Center, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
141
Institute of Human Genetics, Charite Berlin, Campus Virchov Klinikum, 13353, Berlin, Germany.
142
Department of Human Genetics & Department of Clinical Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
143
Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
144
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
145
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0372, Oslo, Norway.
146
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca.

Abstract

PURPOSE:

Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.

METHODS:

Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.

RESULTS:

We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.

CONCLUSION:

We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

KEYWORDS:

BRCA1 and BRCA2 mutation carriers; Breast cancer; Cis-regulatory variants; Differential allelic expression; Genetic modifiers; Genetic susceptibility

PMID:
27796716
PMCID:
PMC5222911
DOI:
10.1007/s10549-016-4018-2
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no conflict of interest. Ethical approval Study participants were recruited through the CIMBA Initiative, following the approval of the corresponding protocol by the Institutional Review Board or Ethics Committee at each participating center. Written informed consent was obtained from all study participants.

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