A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis
A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis
OBJECTIVE:
Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset.
METHODS:
To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10(-8) was used to determine significance. Replication was performed in 1523 additional patients from the POSH study.
RESULTS:
Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10(-6). These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR?=?1.49, 95% confidence interval (CI)?=?1.27-1.75, P?=?1.1×10(-6)), rs12358475 which is between ECHDC3 and PROSER2 (HR?=?0.75, CI?=?0.67-0.85, P?=?1.8×10(-6)), and rs1728400 which is between LINC00917 and FOXF1.
CONCLUSIONS:
In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study
e101488-[10pp]
Miao, Xiaoping
94a8c7d0-aefb-4d86-a8e9-ee76ed34d1a5
Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Khan, Sofia
fd8c8dbd-6ce9-42ee-a322-3faf54aa8685
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Upstill-Goddard, Rosanna
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Gerty, Susan
b2013815-27c9-4a7d-ad42-071f60a8000f
Blomqvist, Carl
31562dd6-3413-40bc-953a-767ae44ff606
Aittomäki, Kristiina
ac3ded8e-805e-4e49-9713-1e03062a2efc
Couch, Fergus J.
778e32f1-0b19-4cf4-b38f-69dd027cad3a
Liu, Jianjun
f6c798ec-5dd6-47b3-a5a2-975ddd6f70d5
Nevanlinna, Heli
69be7a44-2abf-4504-a47b-a50b6723701b
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
19 December 2014
Miao, Xiaoping
94a8c7d0-aefb-4d86-a8e9-ee76ed34d1a5
Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Khan, Sofia
fd8c8dbd-6ce9-42ee-a322-3faf54aa8685
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Upstill-Goddard, Rosanna
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Gerty, Susan
b2013815-27c9-4a7d-ad42-071f60a8000f
Blomqvist, Carl
31562dd6-3413-40bc-953a-767ae44ff606
Aittomäki, Kristiina
ac3ded8e-805e-4e49-9713-1e03062a2efc
Couch, Fergus J.
778e32f1-0b19-4cf4-b38f-69dd027cad3a
Liu, Jianjun
f6c798ec-5dd6-47b3-a5a2-975ddd6f70d5
Nevanlinna, Heli
69be7a44-2abf-4504-a47b-a50b6723701b
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Miao, Xiaoping, Rafiq, Sajjad, Khan, Sofia, Tapper, William, Collins, Andrew, Upstill-Goddard, Rosanna, Gerty, Susan, Blomqvist, Carl, Aittomäki, Kristiina, Couch, Fergus J., Liu, Jianjun, Nevanlinna, Heli and Eccles, Diana
(2014)
A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis.
PLoS ONE, 9 (12), .
(doi:10.1371/journal.pone.0101488).
(PMID:25526632)
Abstract
OBJECTIVE:
Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset.
METHODS:
To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10(-8) was used to determine significance. Replication was performed in 1523 additional patients from the POSH study.
RESULTS:
Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10(-6). These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR?=?1.49, 95% confidence interval (CI)?=?1.27-1.75, P?=?1.1×10(-6)), rs12358475 which is between ECHDC3 and PROSER2 (HR?=?0.75, CI?=?0.67-0.85, P?=?1.8×10(-6)), and rs1728400 which is between LINC00917 and FOXF1.
CONCLUSIONS:
In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study
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Accepted/In Press date: 9 June 2014
Published date: 19 December 2014
Organisations:
Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, Cancer Sciences
Identifiers
Local EPrints ID: 382481
URI: http://eprints.soton.ac.uk/id/eprint/382481
ISSN: 1932-6203
PURE UUID: 091f9214-55c6-4b14-a1cd-4b4d164568c0
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Date deposited: 06 Oct 2015 09:13
Last modified: 15 Mar 2024 03:02
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Contributors
Author:
Xiaoping Miao
Author:
Sajjad Rafiq
Author:
Sofia Khan
Author:
Rosanna Upstill-Goddard
Author:
Susan Gerty
Author:
Carl Blomqvist
Author:
Kristiina Aittomäki
Author:
Fergus J. Couch
Author:
Jianjun Liu
Author:
Heli Nevanlinna
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