Mutation and association analysis of GEN1 in breast cancer susceptibility
Mutation and association analysis of GEN1 in breast cancer susceptibility
GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility
283-288
Turnbull, Clare
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Hines, Sarah
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Renwick, Anthony
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Hughes, Deborah
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Pernet, David
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Elliott, Anna
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Seal, Sheila
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Warren-Perry, Margaret
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Gareth Evans, D.
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Eccles, Diana
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Stratton, Michael R.
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Rahman, Nazneen
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November 2010
Turnbull, Clare
63408861-754b-4f55-a010-29d1bea914e2
Hines, Sarah
033abe1b-bb76-4e1c-aaea-0478a08761cf
Renwick, Anthony
3d9b9053-ec16-41a7-963d-b72f63c44cc9
Hughes, Deborah
fe320510-1e1c-48cb-811e-2abf271cdeed
Pernet, David
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Elliott, Anna
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Seal, Sheila
d8090fdd-aa7a-40c4-a4e4-18a094e7671f
Warren-Perry, Margaret
6aaea312-22e0-4a53-ae1e-c8a14b35005a
Gareth Evans, D.
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Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Stratton, Michael R.
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Rahman, Nazneen
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Turnbull, Clare, Hines, Sarah, Renwick, Anthony, Hughes, Deborah, Pernet, David, Elliott, Anna, Seal, Sheila, Warren-Perry, Margaret, Gareth Evans, D., Eccles, Diana, Stratton, Michael R. and Rahman, Nazneen
(2010)
Mutation and association analysis of GEN1 in breast cancer susceptibility.
Breast Cancer Research and Treatment, 124 (1), .
(doi:10.1007/s10549-010-0949-1).
(PMID:20512659)
Abstract
GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility
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Published date: November 2010
Organisations:
Cancer Sciences, Clinical Trials Unit
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Local EPrints ID: 180169
URI: http://eprints.soton.ac.uk/id/eprint/180169
ISSN: 0167-6806
PURE UUID: 3ebffdcc-3121-4c40-97b0-a23100e8281c
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Date deposited: 05 Apr 2011 14:34
Last modified: 15 Mar 2024 02:40
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Author:
Clare Turnbull
Author:
Sarah Hines
Author:
Anthony Renwick
Author:
Deborah Hughes
Author:
David Pernet
Author:
Anna Elliott
Author:
Sheila Seal
Author:
Margaret Warren-Perry
Author:
D. Gareth Evans
Author:
Michael R. Stratton
Author:
Nazneen Rahman
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