Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou, Olga M Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Susan L Neuhausen, Yuan C Ding, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris BernardPaolo Radice, Csilla I Szabo, Lenka Foretova, Michal Zikan, Kathleen Claes, Mark H Greene, Phuong L Mai, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Hilmi Ozcelik, Gord Glendon, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M Domchek, Zofia Miedzybrodzka, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

Research output: Contribution to journalArticle

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Abstract

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
Original languageEnglish
Pages (from-to)4442-4456
Number of pages15
JournalHuman Molecular Genetics
Volume18
Issue number22
Early online date5 Aug 2009
DOIs
Publication statusPublished - Nov 2009

Fingerprint

Breast Neoplasms
Mutation
Single Nucleotide Polymorphism
Alleles
Population
Genome-Wide Association Study
Case-Control Studies
Odds Ratio
Proteins

Keywords

  • adult
  • aged
  • aged, 80 and over
  • BRCA1 protein
  • BRCA2 protein
  • breast neoplasms
  • chromosomes, human, pair 2
  • chromosomes, human, pair 8
  • female
  • follow-up studies
  • genetic predisposition to disease
  • genetic variation
  • genetics, population
  • genome-wide association study
  • heterozygote
  • humans
  • microfilament proteins
  • middle aged
  • mutation
  • polymorphism, single nucleotide
  • young adult

Cite this

Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., ... Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) (2009). Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics, 18(22), 4442-4456. https://doi.org/10.1093/hmg/ddp372

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. / Antoniou, Antonis C; Sinilnikova, Olga M; McGuffog, Lesley; Healey, Sue; Nevanlinna, Heli; Heikkinen, Tuomas; Simard, Jacques; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L; Ding, Yuan C; Couch, Fergus J; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Peissel, Bernard; Bonanni, Bernardo; Viel, Alessandra; Bernard, Loris; Radice, Paolo; Szabo, Csilla I; Foretova, Lenka; Zikan, Michal; Claes, Kathleen; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L; Ozcelik, Hilmi; Glendon, Gord; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Caligo, Maria A; Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Kaufman, Bella; Dagan, Efrat; Baruch, Ruth Gershoni; Friedman, Eitan; Harbst, Katja; Barbany-Bustinza, Gisela; Rantala, Johanna; Ehrencrona, Hans; Karlsson, Per; Domchek, Susan M; Miedzybrodzka, Zofia (Collaborator); Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab).

In: Human Molecular Genetics, Vol. 18, No. 22, 11.2009, p. 4442-4456.

Research output: Contribution to journalArticle

Antoniou, AC, Sinilnikova, OM, McGuffog, L, Healey, S, Nevanlinna, H, Heikkinen, T, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Neuhausen, SL, Ding, YC, Couch, FJ, Wang, X, Fredericksen, Z, Peterlongo, P, Peissel, B, Bonanni, B, Viel, A, Bernard, L, Radice, P, Szabo, CI, Foretova, L, Zikan, M, Claes, K, Greene, MH, Mai, PL, Rennert, G, Lejbkowicz, F, Andrulis, IL, Ozcelik, H, Glendon, G, Gerdes, A-M, Thomassen, M, Sunde, L, Caligo, MA, Laitman, Y, Kontorovich, T, Cohen, S, Kaufman, B, Dagan, E, Baruch, RG, Friedman, E, Harbst, K, Barbany-Bustinza, G, Rantala, J, Ehrencrona, H, Karlsson, P, Domchek, SM, Miedzybrodzka, Z & Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) 2009, 'Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers', Human Molecular Genetics, vol. 18, no. 22, pp. 4442-4456. https://doi.org/10.1093/hmg/ddp372
Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H, Heikkinen T et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics. 2009 Nov;18(22):4442-4456. https://doi.org/10.1093/hmg/ddp372
Antoniou, Antonis C ; Sinilnikova, Olga M ; McGuffog, Lesley ; Healey, Sue ; Nevanlinna, Heli ; Heikkinen, Tuomas ; Simard, Jacques ; Spurdle, Amanda B ; Beesley, Jonathan ; Chen, Xiaoqing ; Neuhausen, Susan L ; Ding, Yuan C ; Couch, Fergus J ; Wang, Xianshu ; Fredericksen, Zachary ; Peterlongo, Paolo ; Peissel, Bernard ; Bonanni, Bernardo ; Viel, Alessandra ; Bernard, Loris ; Radice, Paolo ; Szabo, Csilla I ; Foretova, Lenka ; Zikan, Michal ; Claes, Kathleen ; Greene, Mark H ; Mai, Phuong L ; Rennert, Gad ; Lejbkowicz, Flavio ; Andrulis, Irene L ; Ozcelik, Hilmi ; Glendon, Gord ; Gerdes, Anne-Marie ; Thomassen, Mads ; Sunde, Lone ; Caligo, Maria A ; Laitman, Yael ; Kontorovich, Tair ; Cohen, Shimrit ; Kaufman, Bella ; Dagan, Efrat ; Baruch, Ruth Gershoni ; Friedman, Eitan ; Harbst, Katja ; Barbany-Bustinza, Gisela ; Rantala, Johanna ; Ehrencrona, Hans ; Karlsson, Per ; Domchek, Susan M ; Miedzybrodzka, Zofia ; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). / Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 22. pp. 4442-4456.
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abstract = "Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95{\%} CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95{\%} CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95{\%} CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95{\%} CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.",
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T1 - Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

AU - Antoniou, Antonis C

AU - Sinilnikova, Olga M

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Nevanlinna, Heli

AU - Heikkinen, Tuomas

AU - Simard, Jacques

AU - Spurdle, Amanda B

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Neuhausen, Susan L

AU - Ding, Yuan C

AU - Couch, Fergus J

AU - Wang, Xianshu

AU - Fredericksen, Zachary

AU - Peterlongo, Paolo

AU - Peissel, Bernard

AU - Bonanni, Bernardo

AU - Viel, Alessandra

AU - Bernard, Loris

AU - Radice, Paolo

AU - Szabo, Csilla I

AU - Foretova, Lenka

AU - Zikan, Michal

AU - Claes, Kathleen

AU - Greene, Mark H

AU - Mai, Phuong L

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Andrulis, Irene L

AU - Ozcelik, Hilmi

AU - Glendon, Gord

AU - Gerdes, Anne-Marie

AU - Thomassen, Mads

AU - Sunde, Lone

AU - Caligo, Maria A

AU - Laitman, Yael

AU - Kontorovich, Tair

AU - Cohen, Shimrit

AU - Kaufman, Bella

AU - Dagan, Efrat

AU - Baruch, Ruth Gershoni

AU - Friedman, Eitan

AU - Harbst, Katja

AU - Barbany-Bustinza, Gisela

AU - Rantala, Johanna

AU - Ehrencrona, Hans

AU - Karlsson, Per

AU - Domchek, Susan M

AU - Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

A2 - Miedzybrodzka, Zofia

PY - 2009/11

Y1 - 2009/11

N2 - Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

AB - Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

KW - adult

KW - aged

KW - aged, 80 and over

KW - BRCA1 protein

KW - BRCA2 protein

KW - breast neoplasms

KW - chromosomes, human, pair 2

KW - chromosomes, human, pair 8

KW - female

KW - follow-up studies

KW - genetic predisposition to disease

KW - genetic variation

KW - genetics, population

KW - genome-wide association study

KW - heterozygote

KW - humans

KW - microfilament proteins

KW - middle aged

KW - mutation

KW - polymorphism, single nucleotide

KW - young adult

U2 - 10.1093/hmg/ddp372

DO - 10.1093/hmg/ddp372

M3 - Article

C2 - 19656774

VL - 18

SP - 4442

EP - 4456

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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