Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Antonis C. Antoniou; Karoline B. Kuchenbaecker; Penny Soucy; Jonathan Beesley; Xiaoqing Chen; Lesley McGuffog; Andrew Lee; Daniel Barrowdale; Sue Healey; Olga M. Sinilnikova; Maria A. Caligo; Niklas Loman; Katja Harbst; Annika Lindblom; Brita Arver; Richard Rosenquist; Per Karlsson; Kate Nathanson; Susan Domchek; Tim Rebbeck; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska; Katarzyna Durda; Elzbieta Zlowowcka-Perlowska; Ana Osorio; Mercedes Duran; Raquel Andres; Javier Benitez; Ute Hamann; Frans B. Hogervorst; Theo A. van Os; Senno Verhoef; Hanne E. J. Meijers-Heijboer; Juul Wijnen; Encarna B. Gomez Garcia; Marjolijn J. Ligtenberg; Mieke Kriege; Margriet Collee; Margreet G. E. M. Ausems; Jan C. Oosterwijk; Susan Peock; Debra Frost; Steve D. Ellis; Radka Platte; Elena Fineberg; D. Gareth Evans; Fiona Lalloo; Chris Jacobs; Ros Eeles; CIMBA Study Collaborator; SWE-BRCA Study Collaborator; HEBON Study Collaborator; EMBRACE Study Collaborator; GEMO Study Collaborator; kConFab Investigators

doi:10.1186/bcr3121

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Antonis C. Antoniou^*, Karoline B. Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Andrew Lee, Daniel Barrowdale, Sue Healey, Olga M. Sinilnikova, Maria A. Caligo, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Richard Rosenquist, Per Karlsson, Kate Nathanson, Susan Domchek, Tim RebbeckAnna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Elzbieta Zlowowcka-Perlowska, Ana Osorio, Mercedes Duran, Raquel Andres, Javier Benitez, Ute Hamann, Frans B. Hogervorst, Theo A. van Os, Senno Verhoef, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gomez Garcia, Marjolijn J. Ligtenberg, Mieke Kriege, Margriet Collee, Margreet G. E. M. Ausems, Jan C. Oosterwijk, Susan Peock, Debra Frost, Steve D. Ellis, Radka Platte, Elena Fineberg, D. Gareth Evans, Fiona Lalloo, Chris Jacobs, Ros Eeles, CIMBA Study Collaborator, SWE-BRCA Study Collaborator, HEBON Study Collaborator, EMBRACE Study Collaborator, GEMO Study Collaborator, kConFab Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Original language	English
Article number	33
Number of pages	18
Journal	Breast cancer research
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/bcr3121
Publication status	Published - 20-Feb-2012

Keywords

GENOME-WIDE ASSOCIATION
HORMONE-RELATED PROTEIN
OVARIAN-CANCER
SUSCEPTIBILITY LOCI
MAMMOGRAPHIC DENSITY
GENETIC MODIFIERS
TUMOR SUBTYPES
ALLELES
CONSORTIUM
INVESTIGATORS

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Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriersFinal publisher's version, 467 KBLicence: CC BY

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Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Lee, A., Barrowdale, D., Healey, S., Sinilnikova, O. M., Caligo, M. A., Loman, N., Harbst, K., Lindblom, A., Arver, B., Rosenquist, R., Karlsson, P., Nathanson, K., Domchek, S., ... kConFab Investigators (2012). Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast cancer research, 14(1), Article 33. https://doi.org/10.1186/bcr3121

@article{1ee42b844bd64395bb91bfb4b95d7016,

title = "Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers",

abstract = "Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.",

keywords = "GENOME-WIDE ASSOCIATION, HORMONE-RELATED PROTEIN, OVARIAN-CANCER, SUSCEPTIBILITY LOCI, MAMMOGRAPHIC DENSITY, GENETIC MODIFIERS, TUMOR SUBTYPES, ALLELES, CONSORTIUM, INVESTIGATORS",

author = "Antoniou, {Antonis C.} and Kuchenbaecker, {Karoline B.} and Penny Soucy and Jonathan Beesley and Xiaoqing Chen and Lesley McGuffog and Andrew Lee and Daniel Barrowdale and Sue Healey and Sinilnikova, {Olga M.} and Caligo, {Maria A.} and Niklas Loman and Katja Harbst and Annika Lindblom and Brita Arver and Richard Rosenquist and Per Karlsson and Kate Nathanson and Susan Domchek and Tim Rebbeck and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska and Katarzyna Durda and Elzbieta Zlowowcka-Perlowska and Ana Osorio and Mercedes Duran and Raquel Andres and Javier Benitez and Ute Hamann and Hogervorst, {Frans B.} and {van Os}, {Theo A.} and Senno Verhoef and Meijers-Heijboer, {Hanne E. J.} and Juul Wijnen and Garcia, {Encarna B. Gomez} and Ligtenberg, {Marjolijn J.} and Mieke Kriege and Margriet Collee and Ausems, {Margreet G. E. M.} and Oosterwijk, {Jan C.} and Susan Peock and Debra Frost and Ellis, {Steve D.} and Radka Platte and Elena Fineberg and Evans, {D. Gareth} and Fiona Lalloo and Chris Jacobs and Ros Eeles and {CIMBA Study Collaborator} and {SWE-BRCA Study Collaborator} and {HEBON Study Collaborator} and {EMBRACE Study Collaborator} and {GEMO Study Collaborator} and {kConFab Investigators}",

year = "2012",

month = feb,

day = "20",

doi = "10.1186/bcr3121",

language = "English",

volume = "14",

journal = "Breast cancer research",

issn = "1465-542X",

publisher = "BioMed Central Ltd.",

number = "1",

}

Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, CIMBA Study Collaborator, SWE-BRCA Study Collaborator, HEBON Study Collaborator, EMBRACE Study Collaborator, GEMO Study Collaborator & kConFab Investigators 2012, 'Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers', Breast cancer research, vol. 14, no. 1, 33. https://doi.org/10.1186/bcr3121

TY - JOUR

T1 - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

AU - Antoniou, Antonis C.

AU - Kuchenbaecker, Karoline B.

AU - Soucy, Penny

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - McGuffog, Lesley

AU - Lee, Andrew

AU - Barrowdale, Daniel

AU - Healey, Sue

AU - Sinilnikova, Olga M.

AU - Caligo, Maria A.

AU - Loman, Niklas

AU - Harbst, Katja

AU - Lindblom, Annika

AU - Arver, Brita

AU - Rosenquist, Richard

AU - Karlsson, Per

AU - Nathanson, Kate

AU - Domchek, Susan

AU - Rebbeck, Tim

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska, Katarzyna

AU - Durda, Katarzyna

AU - Zlowowcka-Perlowska, Elzbieta

AU - Osorio, Ana

AU - Duran, Mercedes

AU - Andres, Raquel

AU - Benitez, Javier

AU - Hamann, Ute

AU - Hogervorst, Frans B.

AU - van Os, Theo A.

AU - Verhoef, Senno

AU - Meijers-Heijboer, Hanne E. J.

AU - Wijnen, Juul

AU - Garcia, Encarna B. Gomez

AU - Ligtenberg, Marjolijn J.

AU - Kriege, Mieke

AU - Collee, Margriet

AU - Ausems, Margreet G. E. M.

AU - Oosterwijk, Jan C.

AU - Peock, Susan

AU - Frost, Debra

AU - Ellis, Steve D.

AU - Platte, Radka

AU - Fineberg, Elena

AU - Evans, D. Gareth

AU - Lalloo, Fiona

AU - Jacobs, Chris

AU - Eeles, Ros

AU - CIMBA Study Collaborator

AU - SWE-BRCA Study Collaborator

AU - HEBON Study Collaborator

AU - EMBRACE Study Collaborator

AU - GEMO Study Collaborator

AU - kConFab Investigators

PY - 2012/2/20

Y1 - 2012/2/20

N2 - Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

AB - Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

KW - GENOME-WIDE ASSOCIATION

KW - HORMONE-RELATED PROTEIN

KW - OVARIAN-CANCER

KW - SUSCEPTIBILITY LOCI

KW - MAMMOGRAPHIC DENSITY

KW - GENETIC MODIFIERS

KW - TUMOR SUBTYPES

KW - ALLELES

KW - CONSORTIUM

KW - INVESTIGATORS

U2 - 10.1186/bcr3121

DO - 10.1186/bcr3121

M3 - Article

SN - 1465-542X

VL - 14

JO - Breast cancer research

JF - Breast cancer research

IS - 1

M1 - 33

ER -