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. 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

Elinor Sawyer  1 , Rebecca Roylance  2 , Christos Petridis  1 , Mark N Brook  3 , Salpie Nowinski  1 , Efterpi Papouli  4 , Olivia Fletcher  5 , Sarah Pinder  1 , Andrew Hanby  6 , Kelly Kohut  2 , Patricia Gorman  2 , Michele Caneppele  2 , Julian Peto  7 , Isabel Dos Santos Silva  7 , Nichola Johnson  5 , Ruth Swann  8 , Miriam Dwek  8 , Katherine-Anne Perkins  8 , Cheryl Gillett  1 , Richard Houlston  3 , Gillian Ross  9 , Paolo De Ieso  9 , Melissa C Southey  10 , John L Hopper  11 , Elena Provenzano  12 , Carmel Apicella  11 , Jelle Wesseling  13 , Sten Cornelissen  13 , Renske Keeman  13 , Peter A Fasching  14 , Sebastian M Jud  15 , Arif B Ekici  16 , Matthias W Beckmann  15 , Michael J Kerin  17 , Federick Marme  18 , Andreas Schneeweiss  18 , Christof Sohn  19 , Barbara Burwinkel  20 , Pascal Guénel  21 , Therese Truong  21 , Pierre Laurent-Puig  22 , Pierre Kerbrat  23 , Stig E Bojesen  24 , Børge G Nordestgaard  24 , Sune F Nielsen  24 , Henrik Flyger  25 , Roger L Milne  26 , Jose Ignacio Arias Perez  27 , Primitiva Menéndez  28 , Javier Benitez  29 , Hermann Brenner  30 , Aida Karina Dieffenbach  30 , Volker Arndt  30 , Christa Stegmaier  31 , Alfons Meindl  32 , Peter Lichtner  33 , Rita K Schmutzler  34 , Magdalena Lochmann  32 , Hiltrud Brauch  35 , Hans-Peter Fischer  36 , Yon-Dschun Ko  37 ; GENICA Network; Heli Nevanlinna  38 , Taru A Muranen  38 , Kristiina Aittomäki  39 , Carl Blomqvist  40 , Natalia V Bogdanova  41 , Thilo Dörk  42 , Annika Lindblom  43 , Sara Margolin  44 , Arto Mannermaa  45 , Vesa Kataja  45 , Veli-Matti Kosma  45 , Jaana M Hartikainen  45 , Georgia Chenevix-Trench  46 ; KConFab Investigators  47 ; Diether Lambrechts  48 , Caroline Weltens  49 , Erik Van Limbergen  49 , Sigrid Hatse  49 , Jenny Chang-Claude  50 , Anja Rudolph  50 , Petra Seibold  50 , Dieter Flesch-Janys  50 , Paolo Radice  51 , Paolo Peterlongo  52 , Bernardo Bonanni  53 , Sara Volorio  54 , Graham G Giles  55 , Gianluca Severi  55 , Laura Baglietto  55 , Catriona A McLean  56 , Christopher A Haiman  57 , Brian E Henderson  57 , Fredrick Schumacher  57 , Loic Le Marchand  58 , Jacques Simard  59 , Mark S Goldberg  60 , France Labrèche  61 , Martine Dumont  59 , Vessela Kristensen  62 , Robert Winqvist  63 , Katri Pylkäs  63 , Arja Jukkola-Vuorinen  64 , Saila Kauppila  64 , Irene L Andrulis  65 , Julia A Knight  66 , Gord Glendon  67 , Anna Marie Mulligan  68 , Peter Devillee  69 , Rob A E M Tollenaar  70 , Caroline M Seynaeve  71 , Mieke Kriege  71 , Jonine Figueroa  72 , Stephen J Chanock  72 , Mark E Sherman  72 , Maartje J Hooning  73 , Antoinette Hollestelle  73 , Ans M W van den Ouweland  74 , Carolien H M van Deurzen  75 , Jingmei Li  76 , Kamila Czene  77 , Keith Humphreys  77 , Angela Cox  78 , Simon S Cross  79 , Malcolm W R Reed  78 , Mitul Shah  80 , Anna Jakubowska  81 , Jan Lubinski  81 , Katarzyna Jaworska-Bieniek  82 , Katarzyna Durda  81 , Anthony Swerdlow  83 , Alan Ashworth  84 , Nicholas Orr  84 , Minouk Schoemaker  3 , Fergus J Couch  85 , Emily Hallberg  86 , Anna González-Neira  87 , Guillermo Pita  87 , M Rosario Alonso  87 , Daniel C Tessier  88 , Daniel Vincent  88 , Francois Bacot  88 , Manjeet K Bolla  89 , Qin Wang  89 , Joe Dennis  89 , Kyriaki Michailidou  89 , Alison M Dunning  80 , Per Hall  77 , Doug Easton  89 , Paul Pharoah  90 , Marjanka K Schmidt  13 , Ian Tomlinson  91 , Montserrat Garcia-Closas  92
Affiliations

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

Elinor Sawyer et al. PLoS Genet. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Lobular cancer study design.
Figure 2
Figure 2. Forest plot for rs11977670.
See this image and copyright information in PMC

References

    1. Yoder BJ, Wilkinson EJ, Massoll NA (2007) Molecular and morphologic distinctions between infiltrating ductal and lobular carcinoma of the breast. Breast J 13 (2) 172–79. - PubMed
    1. Reeves GK, Beral V, Green J, Gathani T (2006) Bull D (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7: 910–918. - PubMed
    1. Kotsopoulos J, Chen WY, Gates MA, Tworoger SS, Hankinson SE, et al. (2010) Risk factors for ductal and lobular breast cancer: results from the nurses' health study. Breast Cancer Res 12: R106. - PMC - PubMed
    1. Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, et al. (2008) Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol 26 (18) 3006–3014. - PubMed
    1. Cristofanilli M, Gonzalez-Angulo A, Sneige N, Kau SW, Broglio K, et al. (2005) Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 1;23 (1) 41–48. - PubMed

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