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Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer

Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer
Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer
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.
1949-2553
4249-4257
Khan, Sofia
3f6723e2-6ef9-4201-b6fa-02d67ced3fd0
Fagerholm, Rainer
fc185b28-c6c8-466a-990a-b7226b62a929
Perunthadambil Kadalayil, Latha
e620b801-844a-45d9-acaf-e0a58acd7cf2
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Aittomäki, Kristiina
ac3ded8e-805e-4e49-9713-1e03062a2efc
Liu, Jianjun
159e7600-f43c-4e46-b907-20e8a7aed9ec
Blomqvist, Carl
10b44d2d-d74b-414f-b163-b5adc59dcaaf
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Nevanlinna, Heli
dcece308-e659-4de6-86b4-810564826f25
Khan, Sofia
3f6723e2-6ef9-4201-b6fa-02d67ced3fd0
Fagerholm, Rainer
fc185b28-c6c8-466a-990a-b7226b62a929
Perunthadambil Kadalayil, Latha
e620b801-844a-45d9-acaf-e0a58acd7cf2
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Aittomäki, Kristiina
ac3ded8e-805e-4e49-9713-1e03062a2efc
Liu, Jianjun
159e7600-f43c-4e46-b907-20e8a7aed9ec
Blomqvist, Carl
10b44d2d-d74b-414f-b163-b5adc59dcaaf
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Nevanlinna, Heli
dcece308-e659-4de6-86b4-810564826f25

Khan, Sofia, Fagerholm, Rainer, Perunthadambil Kadalayil, Latha, Tapper, William, Aittomäki, Kristiina, Liu, Jianjun, Blomqvist, Carl, Eccles, Diana and Nevanlinna, Heli (2018) Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer. Oncotarget, 9 (3), 4249-4257. (doi:10.18632/oncotarget.22747).

Record type: Article

Abstract

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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Accepted/In Press date: 9 November 2017
e-pub ahead of print date: 28 November 2017
Published date: 2018

Identifiers

Local EPrints ID: 417371
URI: https://eprints.soton.ac.uk/id/eprint/417371
ISSN: 1949-2553
PURE UUID: a6accd9c-4a81-4b85-a312-3e8f999f2aa6

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Date deposited: 30 Jan 2018 17:30
Last modified: 09 Mar 2018 17:31

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Contributors

Author: Sofia Khan
Author: Rainer Fagerholm
Author: Latha Perunthadambil Kadalayil
Author: William Tapper
Author: Kristiina Aittomäki
Author: Jianjun Liu
Author: Carl Blomqvist
Author: Diana Eccles
Author: Heli Nevanlinna

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