Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer
Authors: Milne Roger L. , Goode Ellen L. , García-Closas Montserrat , Couch Fergus J. , Severi Gianluca , Hein Rebecca , Fredericksen Zachary , Malats Núria , Zamora M. Pilar , Pérez Jose Ignacio Arias , Benítez Javier , Dörk Thilo , Schürmann Peter , Karstens Johann H. , Hillemanns Peter , Cox Angela , Brock Ian W. , Elliot Graeme , Cross Simon S. , Seal Sheila , Turnbull Clare , Renwick Anthony , Rahman Nazneen , Shen Chen-Yang , Yu Jyh-Cherng , Huang Chiun-Sheng , Hou Ming-Feng , Nordestgaard Børge G. , Bojesen Stig E. , Lanng Charlotte , Alnæs Grethe Grenaker , Kristensen Vessela , Børrensen-Dale Anne-Lise , Hopper John L. , Dite Gillian S. , Apicella Carmel , Southey Melissa C. , Lambrechts Diether , Yesilyurt Betül T. , Floris Giuseppe , Leunen Karin , Sangrajrang Suleeporn , Gaborieau Valerie , Brennan Paul , McKay James , Chang-Claude Jenny , Wang-Gohrke Shan , Radice Paolo , Peterlongo Paolo , Manoukian Siranoush , Barile Monica , Giles Graham G. , Baglietto Laura , John Esther M. , Miron Alexander , Chanock Stephen J. , Lissowska Jolanta , Sherman Mark E. , Figueroa Jonine D. , Bogdanova Natalia V. , Antonenkova Natalia N. , Zalutsky Iosif V. , Rogov Yuri I. , Fasching Peter A. , Bayer Christian M. , Ekici Arif B. , Beckmann Matthias W. , Brenner Hermann , Müller Heiko , Arndt Volker , Stegmaier Christa , Andrulis Irene L. , Knight Julia A. , Glendon Gord , Mulligan Anna Marie , Mannermaa Arto , Kataja Vesa , Kosma Veli-Matti , Hartikainen Jaana M. , Meindl Alfons , Heil Joerg , Bartram Claus R. , Schmutzler Rita K. , Thomas Gilles D. , Hoover Robert N. , Fletcher Olivia , Gibson Lorna J. , dos Santos Silva Isabel , Peto Julian , Nickels Stefan , Flesch-Janys Dieter , Anton-Culver Hoda , Ziogas Argyrios , Sawyer Elinor , Tomlinson Ian , Kerin Michael , Miller Nicola , Schmidt Marjanka K. , Broeks Annegien , Van ‘t Veer Laura J. , Tollenaar Rob A.E.M. , Pharoah Paul D.P. , Dunning Alison M. , Pooley Karen A. , Marme Frederik , Schneeweiss Andreas , Sohn Christof , Burwinkel Barbara , Jakubowska Anna , Lubinski Jan , Jaworska Katarzyna , Durda Katarzyna , Kang Daehee , Yoo Keun-Young , Noh Dong-Young , Ahn Sei-Hyun , Hunter David J. , Hankinson Susan E. , Kraft Peter , Lindstrom Sara , Chen Xiaoqing , Beesley Jonathan , Hamann Ute , Harth Volker , Justenhoven Christina ,   for the GENICA Network, Winqvist Robert , Pylkäs Katri , Jukkola-Vuorinen Arja , Grip Mervi , Hooning Maartje , Hollestelle Antoinette , Oldenburg Rogier A. , Tilanus-Linthorst Madeleine , Khusnutdinova Elza , Bermisheva Marina , Prokofieva Darya , Farahtdinova Albina , Olson Janet E. , Wang Xianshu , Humphreys Manjeet K. , Wang Qin , Chenevix-Trench Georgia , Easton Douglas F. 
Published: October 2011

Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.

Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.

Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7].

Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.

Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.