Open Access Highly Accessed Open Badges Research article

A genome-wide association scan on estrogen receptor-negative breast cancer

Jingmei Li12, Keith Humphreys1, Hatef Darabi1, Gustaf Rosin3, Ulf Hannelius1, Tuomas Heikkinen4, Kristiina Aittomäki5, Carl Blomqvist6, Paul DP Pharoah78, Alison M Dunning8, Shahana Ahmed8, Maartje J Hooning9, Antoinette Hollestelle10, Rogier A Oldenburg11, Lars Alfredsson12, Aarno Palotie13141516, Leena Peltonen-Palotie13141516, Astrid Irwanto2, Hui Qi Low2, Garrett HK Teoh2, Anbupalam Thalamuthu2, Juha Kere1718193, Mauro D'Amato3, Douglas F Easton78, Heli Nevanlinna4, Jianjun Liu2*, Kamila Czene1 and Per Hall1*

Author Affiliations

1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, P.O. Box 281, Stockholm 17177, Sweden

2 Human Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore

3 Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7-9, Novum, SE-141 81, Huddinge, Sweden

4 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 700, 00029 HUS, Helsinki, Finland

5 Department of Clinical Genetics, Helsinki University Central Hospital, Haartmanink 2 B, 00029 HUS, Helsinki, Finland

6 Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, 00029 HUS, Helsinki, Finland

7 Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK

8 Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK

9 Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, Netherlands

10 Department of Medical Oncology, Erasmus University Medical Center, Josephine Nefkens Institute, Dr. Molenwaterplein 50, 3015 GE Rotterdam, The Netherlands

11 Department of Clinical Genetics, Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Dr. Molenwaterplein 50, 3015 GE Rotterdam, Netherlands

12 Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 281, Stockholm 17177, Sweden

13 Institute for Molecular Medicine Finland, FIMM, University of Helsinki, P.O. Box 20, FI-00014, Finland

14 Public Health Genomics Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland

15 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

16 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA

17 Clinical Research Centre, Karolinska Institute, Karolinska University Hospital Huddinge, SE-141 86, Huddinge, Sweden

18 Department of Medical Genetics, University of Helsinki, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014, Finland

19 Folkhälsan Institute of Genetics, Folkhälsan Research Center; University of Helsinki, Haartmaninkatu 8, Biomedicum 1, P.O. Box 63, FI-00014, Finland

For all author emails, please log on.

Breast Cancer Research 2010, 12:R93  doi:10.1186/bcr2772

Published: 9 November 2010



Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.


We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.


Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.


ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.