Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer
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Sofia Khan1, Rainer Fagerholm1, Latha Kadalayil2,3, William Tapper2, Kristiina Aittomäki4, Jianjun Liu5,6, Carl Blomqvist7,8,*, Diana Eccles2,* and Heli Nevanlinna1,*
1Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Biomedicum, Helsinki, Finland
2Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
3Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK
4Department of Clinical Genetics, Helsinki University Hospital and Genome Scale Biology Research Program, University of Helsinki, Helsinki, Finland
5Human Genetics, Genome Institute of Singapore, Singapore
6Yong Loo Lin School of Medicine, National University of Singapore, Singapore
7Department of Oncology, Helsinki University Hospital, Helsinki, Finland
8Department of Oncology, University of Örebro, Örebro, Sweden
*These authors contributed equally to this work
Heli Nevanlinna, email: [email protected]
Keywords: breast cancer; endocrine therapy; tamoxifen; GWAS; survival
Received: June 22, 2017 Accepted: November 09, 2017 Published: November 28, 2017
The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 × 10−8). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 × 10−8). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79–27.08, Pinteraction = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.
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