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PLoS Genet. 2014 Apr 17;10(4):e1004285. doi: 10.1371/journal.pgen.1004285. eCollection 2014 Apr.

Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Sawyer E1, Roylance R2, Petridis C1, Brook MN3, Nowinski S1, Papouli E4, Fletcher O5, Pinder S1, Hanby A6, Kohut K2, Gorman P2, Caneppele M2, Peto J7, Dos Santos Silva I7, Johnson N5, Swann R8, Dwek M8, Perkins KA8, Gillett C1, Houlston R3, Ross G9, De Ieso P9, Southey MC10, Hopper JL11, Provenzano E12, Apicella C11, Wesseling J13, Cornelissen S13, Keeman R13, Fasching PA14, Jud SM15, Ekici AB16, Beckmann MW15, Kerin MJ17, Marme F18, Schneeweiss A18, Sohn C19, Burwinkel B20, Guénel P21, Truong T21, Laurent-Puig P22, Kerbrat P23, Bojesen SE24, Nordestgaard BG24, Nielsen SF24, Flyger H25, Milne RL26, Perez JI27, Menéndez P28, Benitez J29, Brenner H30, Dieffenbach AK30, Arndt V30, Stegmaier C31, Meindl A32, Lichtner P33, Schmutzler RK34, Lochmann M32, Brauch H35, Fischer HP36, Ko YD37; GENICA Network, Nevanlinna H38, Muranen TA38, Aittomäki K39, Blomqvist C40, Bogdanova NV41, Dörk T42, Lindblom A43, Margolin S44, Mannermaa A45, Kataja V45, Kosma VM45, Hartikainen JM45, Chenevix-Trench G46, Investigators K47, Lambrechts D48, Weltens C49, Van Limbergen E49, Hatse S49, Chang-Claude J50, Rudolph A50, Seibold P50, Flesch-Janys D50, Radice P51, Peterlongo P52, Bonanni B53, Volorio S54, Giles GG55, Severi G55, Baglietto L55, McLean CA56, Haiman CA57, Henderson BE57, Schumacher F57, Le Marchand L58, Simard J59, Goldberg MS60, Labrèche F61, Dumont M59, Kristensen V62, Winqvist R63, Pylkäs K63, Jukkola-Vuorinen A64, Kauppila S64, Andrulis IL65, Knight JA66, Glendon G67, Mulligan AM68, Devillee P69, Tollenaar RA70, Seynaeve CM71, Kriege M71, Figueroa J72, Chanock SJ72, Sherman ME72, Hooning MJ73, Hollestelle A73, van den Ouweland AM74, van Deurzen CH75, Li J76, Czene K77, Humphreys K77, Cox A78, Cross SS79, Reed MW78, Shah M80, Jakubowska A81, Lubinski J81, Jaworska-Bieniek K82, Durda K81, Swerdlow A83, Ashworth A84, Orr N84, Schoemaker M3, Couch FJ85, Hallberg E86, González-Neira A87, Pita G87, Alonso MR87, Tessier DC88, Vincent D88, Bacot F88, Bolla MK89, Wang Q89, Dennis J89, Michailidou K89, Dunning AM80, Hall P77, Easton D89, Pharoah P90, Schmidt MK13, Tomlinson I91, Garcia-Closas M92.

Author information

1
Research Oncology, Division of Cancer Studies, Kings College London, Guy's Hospital, London, United Kingdom.
2
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
3
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
4
Biomedical Research Centre, King's College London, Guy's Hospital, London, United Kingdom.
5
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
6
Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom.
7
London School of Hygiene and Tropical Medicine, London, United Kingdom.
8
Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom.
9
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
10
Department of Pathology, The University of Melbourne, Melbourne, Australia.
11
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia.
12
NIHR Cambridge Biomedical Research Centre, Addenbrookes Hospital, Cambridge, United Kingdom.
13
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
14
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
15
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
16
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
17
Surgery, Clinical Science Institute, National University of Ireland, Galway, Ireland.
18
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
19
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
20
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany; Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
21
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France; University Paris-Sud, UMRS 1018, Villejuif, France.
22
Université Paris Sorbonne Cité, UMR-S775 Inserm, Paris, France.
23
Centre Eugène Marquis, Department of Medical Oncology, Rennes, France.
24
Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
25
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
26
Genetic & Molecular Epidemiology Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre [CNIO], Madrid, Spain.
27
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
28
Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
29
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre [CNIO], Madrid, Spain.
30
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
31
Saarland Cancer Registry, Saarbrücken, Germany.
32
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
33
Institute of Human Genetics, Technische Universität, Munich, Germany.
34
Centre for Familial Breast and Ovarian Cancer and Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
35
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
36
Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany.
37
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
38
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
39
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
40
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
41
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
42
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
43
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
44
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
45
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Joensuu, Finland; Cancer Center, Kuopio University Hospital, Kuopio, Finland.
46
Department of Genetics, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
47
Peter MacCallum Cancer Center, Melbourne, Australia.
48
Vesalius Research Center (VRC), VIB, Leuven, Belgium; Department of Oncology, University of Leuven, Leuven, Belgium.
49
University Hospital Gashuisberg, Leuven, Belgium.
50
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
51
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
52
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
53
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
54
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
55
Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia; Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia.
56
Department of Pathology, The Alfred Hospital, Prahran, Victoria, Australia.
57
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
58
Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, United States of America.
59
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec, Canada.
60
Department of Medicine, McGill University, Montreal, Quebec, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada.
61
Département de médecine sociale et préventive, Département de santé environnementale et santé au travail, Université de Montréal, Montreal, Quebec, Canada.
62
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway; Faculty of Medicine (Faculty Division Ahus), UiO, Oslo, Norway.
63
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab/Oulu University Hospital, Oulu, Finland.
64
Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
65
Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
66
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
67
Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
68
Laboratory Medicine Program, University Health Network, Toronto, Ontario; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
69
Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
70
Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
71
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
72
Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, United States of America.
73
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
74
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
75
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
76
Human Genetics Division, Genome Institute of Singapore, Singapore.
77
Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
78
CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
79
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
80
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
81
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
82
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
83
Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
84
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
85
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
86
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
87
Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre [CNIO], Madrid, Spain.
88
McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
89
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
90
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
91
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
92
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom; Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.

Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

PMID:
24743323
PMCID:
PMC3990493
DOI:
10.1371/journal.pgen.1004285
[Indexed for MEDLINE]
Free PMC Article

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