Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

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 = 6.0610210; P-het for ILC vs IDC ER+ tumors = 1.861024 ). 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, Phet = 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.

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Item Type:	Article
Authors/Creators:	Sawyer, E. Roylance, R. Petridis, C. Brook, M.N. Nowinski, S. Papouli, E. Fletcher, O. Pinder, S. Hanby, A. Kohut, K. Gorman, P. Caneppele, M. Peto, J. Silva, I.D.S. Johnson, N. Swann, R. Dwek, M. Perkins, K-A. Gillett, C. Houlston, R. Ross, G. De Ieso, P. Southey, M.C. Hopper, J.L. Provenzano, E. Apicella, C. Wesseling, J. Cornelissen, S. Keeman, R. Fasching, P.A. Jud, S.M. Ekici, A.B. Beckmann, M.W. Kerin, M.J. Marme, F. Schneeweiss, A. Sohn, C. Burwinkel, B. Guenel, P. Truong, T. Laurent-Puig, P. Kerbrat, P. Bojesen, S.E. Nordestgaard, B.G. Nielsen, S.F. Flyger, H. Milne, R.L. Perez, J.I.A. Menendez, P. Benitez, J. Brenner, H. Dieffenbach, A.K. Arndt, V. Stegmaier, C. Meindl, A. Lichtner, P. Schmutzler, R.K. Lochmann, M. Brauch, H. Fischer, H-P. Ko, Y-D. Nevanlinna, H. Muranen, T.A. Aittomaki, K. Blomqvist, C. Bogdanova, N.V. Dork, T. Lindblom, A. Margolin, S. Mannermaa, A. Kataja, V. Kosma, V-M. Hartikainen, J.M. Chenevix-Trench, G. Lambrechts, D. Weltens, C. Van Limbergen, E. Hatse, S. Chang-Claude, J. Rudolph, A. Seibold, P. Flesch-Janys, D. Radice, P. Peterlongo, P. Bonanni, B. Volorio, S. Giles, G.G. Severi, G. Baglietto, L. Mclean, C.A. Haiman, C.A. Henderson, B.E. Schumacher, F. Le Marchand, L. Simard, J. Goldberg, M.S. Labreche, F. Dumont, M. Kristensen, V. Winqvist, R. Pylkas, K. Jukkola-Vuorinen, A. Kauppila, S. Andrulis, I.L. Knight, J.A. Glendon, G. Mulligan, A.M. Devillee, P. Tollenaar, R.A.E.M. Seynaeve, C.M. Kriege, M. Figueroa, J. Chanock, S.J. Sherman, M.E. Hooning, M.J. Hollestelle, A. van den Ouweland, A.M.W. van Deurzen, C.H.M. Li, J. Czene, K. Humphreys, K. Cox, A. https://orcid.org/0000-0002-5138-1099 Cross, S.S. https://orcid.org/0000-0003-2044-1754 Reed, M.W.R. Shah, M. Jakubowska, A. Lubinski, J. Jaworska-Bieniek, K. Durda, K. Swerdlow, A. Ashworth, A. Orr, N. Schoemaker, M. Couch, F.J. Hallberg, E. Gonzalez-Neira, A. Pita, G. Alonso, M.R. Tessier, D.C. Vincent, D. Bacot, F. Bolla, M.K. Wang, Q. Dennis, J. Michailidou, K. Dunning, A.M. Hall, P. Easton, D. Pharoah, P. Schmidt, M.K. Tomlinson, I. Garcia-Closas, M. Network, GENICA Investigators, K
Copyright, Publisher and Additional Information:	© This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Dates:	Published: 17 April 2014 Accepted: 17 February 2014
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	15 Apr 2016 09:33
Last Modified:	15 Apr 2016 09:33
Published Version:	http://dx.doi.org/10.1371/journal.pgen.1004285
Status:	Published
Publisher:	Public Library of Science
Refereed:	Yes
Identification Number:	10.1371/journal.pgen.1004285
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:97458

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Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

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