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

Jingmei Li, Keith Humphreys, Hatef Darabi, Gustaf Rosin, Ulf Hannelius, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Paul D.P. Pharoah, Alison M. Dunning, Shahana Ahmed, Maartje J. Hooning, Antoinette Hollestelle, Rogier A. Oldenburg, Lars Alfredsson, Aarno Palotie, Leena Peltonen-Palotie, Astrid Irwanto, Hui Q. Low, Garrett H.K. TeohAnbupalam Thalamuthu, Juha Kere, Mauro D'Amato, Douglas F. Easton, Heli Nevanlinna, Jianjun Liu, Kamila Czene, Per Hall

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Introduction: 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.Methods: 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.Results: 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.Conclusions: 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.

Original languageEnglish
Article numberR93
JournalBreast Cancer Research
Issue number6
Publication statusPublished - 9 Nov 2010
Externally publishedYes

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