Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou, Christiana Kartsonaki, Olga M Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice & 31 others Phuong L Mai, Mark H Greene, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Uffe Birk Jensen, Dorthe G Crüger, Maria A Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, Katherine L Nathanson, Susan M Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Zosia Miedzybrodzka, SWE-BRCA

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Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
Original languageEnglish
Pages (from-to)3304-3321
Number of pages18
JournalHuman Molecular Genetics
Volume20
Issue number16
Early online date18 May 2011
DOIs
Publication statusPublished - 15 Aug 2011

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Alleles
Breast Neoplasms
Single Nucleotide Polymorphism
Mutation
Confidence Intervals
Genome-Wide Association Study
Research Personnel
Genes
Neoplasms

Keywords

  • adult
  • aged
  • alleles
  • BRCA1 protein
  • BRCA2 protein
  • breast neoplasms
  • chromosomes, human
  • chromosomes, human, pair 1
  • chromosomes, human, pair 6
  • female
  • genetic predisposition to disease
  • heterozygote
  • humans
  • middle aged
  • mutation
  • polymorphism, single nucleotide
  • risk factors

Cite this

Antoniou, A. C., Kartsonaki, C., Sinilnikova, O. M., Soucy, P., McGuffog, L., Healey, S., ... SWE-BRCA (2011). Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics, 20(16), 3304-3321. https://doi.org/10.1093/hmg/ddr226

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. / Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Putignano, Anna Laura; Varesco, Liliana; Radice, Paolo; Mai, Phuong L; Greene, Mark H; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Birk Jensen, Uffe; Crüger, Dorthe G; Caligo, Maria A; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Miedzybrodzka, Zosia; SWE-BRCA.

In: Human Molecular Genetics, Vol. 20, No. 16, 15.08.2011, p. 3304-3321.

Research output: Contribution to journalArticle

Antoniou, AC, Kartsonaki, C, Sinilnikova, OM, Soucy, P, McGuffog, L, Healey, S, Lee, A, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Barile, M, Pensotti, V, Pasini, B, Dolcetti, R, Giannini, G, Putignano, AL, Varesco, L, Radice, P, Mai, PL, Greene, MH, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A-M, Kruse, TA, Birk Jensen, U, Crüger, DG, Caligo, MA, Laitman, Y, Milgrom, R, Kaufman, B, Paluch-Shimon, S, Friedman, E, Loman, N, Harbst, K, Lindblom, A, Arver, B, Ehrencrona, H, Melin, B, Nathanson, KL, Domchek, SM, Rebbeck, T, Jakubowska, A, Lubinski, J, Gronwald, J, Huzarski, T, Miedzybrodzka, Z & SWE-BRCA 2011, 'Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers', Human Molecular Genetics, vol. 20, no. 16, pp. 3304-3321. https://doi.org/10.1093/hmg/ddr226
Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L, Healey S et al. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics. 2011 Aug 15;20(16):3304-3321. https://doi.org/10.1093/hmg/ddr226
Antoniou, Antonis C ; Kartsonaki, Christiana ; Sinilnikova, Olga M ; Soucy, Penny ; McGuffog, Lesley ; Healey, Sue ; Lee, Andrew ; Peterlongo, Paolo ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Cattaneo, Elisa ; Barile, Monica ; Pensotti, Valeria ; Pasini, Barbara ; Dolcetti, Riccardo ; Giannini, Giuseppe ; Putignano, Anna Laura ; Varesco, Liliana ; Radice, Paolo ; Mai, Phuong L ; Greene, Mark H ; Andrulis, Irene L ; Glendon, Gord ; Ozcelik, Hilmi ; Thomassen, Mads ; Gerdes, Anne-Marie ; Kruse, Torben A ; Birk Jensen, Uffe ; Crüger, Dorthe G ; Caligo, Maria A ; Laitman, Yael ; Milgrom, Roni ; Kaufman, Bella ; Paluch-Shimon, Shani ; Friedman, Eitan ; Loman, Niklas ; Harbst, Katja ; Lindblom, Annika ; Arver, Brita ; Ehrencrona, Hans ; Melin, Beatrice ; Nathanson, Katherine L ; Domchek, Susan M ; Rebbeck, Timothy ; Jakubowska, Ania ; Lubinski, Jan ; Gronwald, Jacek ; Huzarski, Tomasz ; Miedzybrodzka, Zosia ; SWE-BRCA. / Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 16. pp. 3304-3321.
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title = "Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers",
abstract = "Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95{\%} confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95{\%} CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95{\%} CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95{\%} CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95{\%} CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.",
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author = "Antoniou, {Antonis C} and Christiana Kartsonaki and Sinilnikova, {Olga M} and Penny Soucy and Lesley McGuffog and Sue Healey and Andrew Lee and Paolo Peterlongo and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Elisa Cattaneo and Monica Barile and Valeria Pensotti and Barbara Pasini and Riccardo Dolcetti and Giuseppe Giannini and Putignano, {Anna Laura} and Liliana Varesco and Paolo Radice and Mai, {Phuong L} and Greene, {Mark H} and Andrulis, {Irene L} and Gord Glendon and Hilmi Ozcelik and Mads Thomassen and Anne-Marie Gerdes and Kruse, {Torben A} and {Birk Jensen}, Uffe and Cr{\"u}ger, {Dorthe G} and Caligo, {Maria A} and Yael Laitman and Roni Milgrom and Bella Kaufman and Shani Paluch-Shimon and Eitan Friedman and Niklas Loman and Katja Harbst and Annika Lindblom and Brita Arver and Hans Ehrencrona and Beatrice Melin and Nathanson, {Katherine L} and Domchek, {Susan M} and Timothy Rebbeck and Ania Jakubowska and Jan Lubinski and Jacek Gronwald and Tomasz Huzarski and Zosia Miedzybrodzka and SWE-BRCA",
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TY - JOUR

T1 - Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

AU - Antoniou, Antonis C

AU - Kartsonaki, Christiana

AU - Sinilnikova, Olga M

AU - Soucy, Penny

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Lee, Andrew

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Cattaneo, Elisa

AU - Barile, Monica

AU - Pensotti, Valeria

AU - Pasini, Barbara

AU - Dolcetti, Riccardo

AU - Giannini, Giuseppe

AU - Putignano, Anna Laura

AU - Varesco, Liliana

AU - Radice, Paolo

AU - Mai, Phuong L

AU - Greene, Mark H

AU - Andrulis, Irene L

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Kruse, Torben A

AU - Birk Jensen, Uffe

AU - Crüger, Dorthe G

AU - Caligo, Maria A

AU - Laitman, Yael

AU - Milgrom, Roni

AU - Kaufman, Bella

AU - Paluch-Shimon, Shani

AU - Friedman, Eitan

AU - Loman, Niklas

AU - Harbst, Katja

AU - Lindblom, Annika

AU - Arver, Brita

AU - Ehrencrona, Hans

AU - Melin, Beatrice

AU - Nathanson, Katherine L

AU - Domchek, Susan M

AU - Rebbeck, Timothy

AU - Jakubowska, Ania

AU - Lubinski, Jan

AU - Gronwald, Jacek

AU - Huzarski, Tomasz

AU - Miedzybrodzka, Zosia

AU - SWE-BRCA

PY - 2011/8/15

Y1 - 2011/8/15

N2 - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

AB - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

KW - adult

KW - aged

KW - alleles

KW - BRCA1 protein

KW - BRCA2 protein

KW - breast neoplasms

KW - chromosomes, human

KW - chromosomes, human, pair 1

KW - chromosomes, human, pair 6

KW - female

KW - genetic predisposition to disease

KW - heterozygote

KW - humans

KW - middle aged

KW - mutation

KW - polymorphism, single nucleotide

KW - risk factors

U2 - 10.1093/hmg/ddr226

DO - 10.1093/hmg/ddr226

M3 - Article

VL - 20

SP - 3304

EP - 3321

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

ER -