Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression

identification of a modifier of breast cancer risk at locus 11q22.3

Yosr Hamdi, Penny Soucy, Karoline B Kuchenbaeker, Tomi Pastinen, Arnaud Droit, Audrey Lemaçon, Julian Adlard, Kristiina Aittomäki, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Banu K Arun, Jacopo Azzollini, Anita Bane, Laure Barjhoux, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Marinus J Blok, Kristie Bobolis & 30 others Valérie Bonadona, Bernardo Bonanni, Angela R Bradbury, Carole Brewer, Bruno Buecher, Saundra S Buys, Maria A Caligo, Jocelyne Chiquette, Wendy K Chung, Kathleen B M Claes, Mary B Daly, Francesca Damiola, Rosemarie Davidson, Miguel De la Hoya, Kim De Leeneer, Orland Diez, Yuan Chun Ding, Riccardo Dolcetti, Susan M Domchek, Cecilia M Dorfling, Diana Eccles, Ros Eeles, Zakaria Einbeigi, Bent Ejlertsen, Christoph Engel, Siranoush Manoukian, Marco Montagna, Bernard Peissel, Paolo Radice, Silvia Tognazzo

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.

METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.

RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.

CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Original languageEnglish
Pages (from-to)117-134
Number of pages18
JournalBreast Cancer Research and Treatment
Volume161
Issue number1
DOIs
Publication statusPublished - Jan 2017

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Heterozygote
Single Nucleotide Polymorphism
Breast Neoplasms
Mutation
Estrogen Receptors
Genes
Quantitative Trait Loci
Progesterone Receptors
Computer Simulation
Ovarian Neoplasms
Breast
Research Personnel
Genome
Neoplasms

Keywords

  • Alleles
  • Biomarkers, Tumor
  • Breast Neoplasms/epidemiology
  • Chromosomes, Human, Pair 11
  • Female
  • Gene Expression
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Mutation
  • Quantitative Trait Loci
  • Risk

Cite this

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3. / Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Azzollini, Jacopo; Bane, Anita; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J; Bobolis, Kristie; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caligo, Maria A; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; De la Hoya, Miguel; De Leeneer, Kim; Diez, Orland; Ding, Yuan Chun; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Eccles, Diana; Eeles, Ros; Einbeigi, Zakaria; Ejlertsen, Bent; Engel, Christoph; Manoukian, Siranoush; Montagna, Marco; Peissel, Bernard; Radice, Paolo; Tognazzo, Silvia.

In: Breast Cancer Research and Treatment, Vol. 161, No. 1, 01.2017, p. 117-134.

Research output: Contribution to journalArticle

Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemaçon, A, Adlard, J, Aittomäki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Manoukian, S, Montagna, M, Peissel, B, Radice, P & Tognazzo, S 2017, 'Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3', Breast Cancer Research and Treatment, vol. 161, no. 1, pp. 117-134. https://doi.org/10.1007/s10549-016-4018-2
Hamdi, Yosr ; Soucy, Penny ; Kuchenbaeker, Karoline B ; Pastinen, Tomi ; Droit, Arnaud ; Lemaçon, Audrey ; Adlard, Julian ; Aittomäki, Kristiina ; Andrulis, Irene L ; Arason, Adalgeir ; Arnold, Norbert ; Arun, Banu K ; Azzollini, Jacopo ; Bane, Anita ; Barjhoux, Laure ; Barrowdale, Daniel ; Benitez, Javier ; Berthet, Pascaline ; Blok, Marinus J ; Bobolis, Kristie ; Bonadona, Valérie ; Bonanni, Bernardo ; Bradbury, Angela R ; Brewer, Carole ; Buecher, Bruno ; Buys, Saundra S ; Caligo, Maria A ; Chiquette, Jocelyne ; Chung, Wendy K ; Claes, Kathleen B M ; Daly, Mary B ; Damiola, Francesca ; Davidson, Rosemarie ; De la Hoya, Miguel ; De Leeneer, Kim ; Diez, Orland ; Ding, Yuan Chun ; Dolcetti, Riccardo ; Domchek, Susan M ; Dorfling, Cecilia M ; Eccles, Diana ; Eeles, Ros ; Einbeigi, Zakaria ; Ejlertsen, Bent ; Engel, Christoph ; Manoukian, Siranoush ; Montagna, Marco ; Peissel, Bernard ; Radice, Paolo ; Tognazzo, Silvia. / Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3. In: Breast Cancer Research and Treatment. 2017 ; Vol. 161, No. 1. pp. 117-134.
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title = "Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3",
abstract = "PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.",
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author = "Yosr Hamdi and Penny Soucy and Kuchenbaeker, {Karoline B} and Tomi Pastinen and Arnaud Droit and Audrey Lema{\cc}on and Julian Adlard and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Adalgeir Arason and Norbert Arnold and Arun, {Banu K} and Jacopo Azzollini and Anita Bane and Laure Barjhoux and Daniel Barrowdale and Javier Benitez and Pascaline Berthet and Blok, {Marinus J} and Kristie Bobolis and Val{\'e}rie Bonadona and Bernardo Bonanni and Bradbury, {Angela R} and Carole Brewer and Bruno Buecher and Buys, {Saundra S} and Caligo, {Maria A} and Jocelyne Chiquette and Chung, {Wendy K} and Claes, {Kathleen B M} and Daly, {Mary B} and Francesca Damiola and Rosemarie Davidson and {De la Hoya}, Miguel and {De Leeneer}, Kim and Orland Diez and Ding, {Yuan Chun} and Riccardo Dolcetti and Domchek, {Susan M} and Dorfling, {Cecilia M} and Diana Eccles and Ros Eeles and Zakaria Einbeigi and Bent Ejlertsen and Christoph Engel and Siranoush Manoukian and Marco Montagna and Bernard Peissel and Paolo Radice and Silvia Tognazzo",
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TY - JOUR

T1 - Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression

T2 - identification of a modifier of breast cancer risk at locus 11q22.3

AU - Hamdi, Yosr

AU - Soucy, Penny

AU - Kuchenbaeker, Karoline B

AU - Pastinen, Tomi

AU - Droit, Arnaud

AU - Lemaçon, Audrey

AU - Adlard, Julian

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Arason, Adalgeir

AU - Arnold, Norbert

AU - Arun, Banu K

AU - Azzollini, Jacopo

AU - Bane, Anita

AU - Barjhoux, Laure

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berthet, Pascaline

AU - Blok, Marinus J

AU - Bobolis, Kristie

AU - Bonadona, Valérie

AU - Bonanni, Bernardo

AU - Bradbury, Angela R

AU - Brewer, Carole

AU - Buecher, Bruno

AU - Buys, Saundra S

AU - Caligo, Maria A

AU - Chiquette, Jocelyne

AU - Chung, Wendy K

AU - Claes, Kathleen B M

AU - Daly, Mary B

AU - Damiola, Francesca

AU - Davidson, Rosemarie

AU - De la Hoya, Miguel

AU - De Leeneer, Kim

AU - Diez, Orland

AU - Ding, Yuan Chun

AU - Dolcetti, Riccardo

AU - Domchek, Susan M

AU - Dorfling, Cecilia M

AU - Eccles, Diana

AU - Eeles, Ros

AU - Einbeigi, Zakaria

AU - Ejlertsen, Bent

AU - Engel, Christoph

AU - Manoukian, Siranoush

AU - Montagna, Marco

AU - Peissel, Bernard

AU - Radice, Paolo

AU - Tognazzo, Silvia

PY - 2017/1

Y1 - 2017/1

N2 - PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

AB - PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

KW - Alleles

KW - Biomarkers, Tumor

KW - Breast Neoplasms/epidemiology

KW - Chromosomes, Human, Pair 11

KW - Female

KW - Gene Expression

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Quantitative Trait Loci

KW - Risk

U2 - 10.1007/s10549-016-4018-2

DO - 10.1007/s10549-016-4018-2

M3 - Article

VL - 161

SP - 117

EP - 134

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -