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

Elinor J Sawyer, Rebecca Roylance, Christos Petridis, Mark N. Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah E Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine Anne Perkins, Cheryl E Gillett, Richard HoulstonGillian Ross, Paolo De Ieso, Melissa C. Southey, John L. Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A. Fasching, Sebastian M Jud, Arif B Ekici, Matthias W. Beckmann, Michael J. Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G. Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K. Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-Trench, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona A. Mclean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A.E.M. Tollenaar, Caroline M. Seynaeve, Mieke Kriege, Jonine D Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H.M. Van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony J Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul D P Pharoah, Marjanka K. Schmidt, Ian P Tomlinson, Montserrat Garcia-Closas, The GENICA Network, kConFab Investigators

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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.

Original languageEnglish
Article numbere1004285
Number of pages14
JournalPLoS Genetics
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

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