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Identification of inherited genetic variations influencing prognosis in early-onset breast cancer

Identification of inherited genetic variations influencing prognosis in early-onset breast cancer
Identification of inherited genetic variations influencing prognosis in early-onset breast cancer
Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ? 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 × 10(-7)]. Four further associations at or close to the PBX1, ROR?, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis.

0008-5472
1883-1891
Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Khan, Sofia
fd8c8dbd-6ce9-42ee-a322-3faf54aa8685
Politopoulos, Ionnis
b9cbd604-a454-44c3-97c5-8ac5a3c370a5
Gerty, Sue
b2013815-27c9-4a7d-ad42-071f60a8000f
Blomqvist, Carl
31562dd6-3413-40bc-953a-767ae44ff606
Couch, Fergus J.
778e32f1-0b19-4cf4-b38f-69dd027cad3a
Nevanlinna, Heli
69be7a44-2abf-4504-a47b-a50b6723701b
Liu, Jianjun
f6c798ec-5dd6-47b3-a5a2-975ddd6f70d5
Eccles, Diana
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Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Khan, Sofia
fd8c8dbd-6ce9-42ee-a322-3faf54aa8685
Politopoulos, Ionnis
b9cbd604-a454-44c3-97c5-8ac5a3c370a5
Gerty, Sue
b2013815-27c9-4a7d-ad42-071f60a8000f
Blomqvist, Carl
31562dd6-3413-40bc-953a-767ae44ff606
Couch, Fergus J.
778e32f1-0b19-4cf4-b38f-69dd027cad3a
Nevanlinna, Heli
69be7a44-2abf-4504-a47b-a50b6723701b
Liu, Jianjun
f6c798ec-5dd6-47b3-a5a2-975ddd6f70d5
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23

Rafiq, Sajjad, Tapper, William, Collins, Andrew, Khan, Sofia, Politopoulos, Ionnis, Gerty, Sue, Blomqvist, Carl, Couch, Fergus J., Nevanlinna, Heli, Liu, Jianjun and Eccles, Diana (2013) Identification of inherited genetic variations influencing prognosis in early-onset breast cancer. Cancer Research, 73 (6), 1883-1891. (doi:10.1158/0008-5472.CAN-12-3377). (PMID:23319801)

Record type: Article

Abstract

Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ? 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 × 10(-7)]. Four further associations at or close to the PBX1, ROR?, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis.

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More information

e-pub ahead of print date: 14 January 2013
Published date: 15 March 2013
Organisations: Cancer Sciences, Human Development & Health, Clinical Trials Unit

Identifiers

Local EPrints ID: 352313
URI: http://eprints.soton.ac.uk/id/eprint/352313
ISSN: 0008-5472
PURE UUID: ec50bd30-8ead-499c-9c3f-540fd2686951
ORCID for William Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 09 May 2013 10:17
Last modified: 23 Jul 2022 01:45

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Contributors

Author: Sajjad Rafiq
Author: William Tapper ORCID iD
Author: Andrew Collins ORCID iD
Author: Sofia Khan
Author: Ionnis Politopoulos
Author: Sue Gerty
Author: Carl Blomqvist
Author: Fergus J. Couch
Author: Heli Nevanlinna
Author: Jianjun Liu
Author: Diana Eccles ORCID iD

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