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; Jacopo Azzollini; Banu K Arun; Anita Bane; Laure Barjhoux; Daniel Barrowdale; Javier Benitez; Pascaline Berthet; Marinus J Blok; Kristie A Bobolis; Valérie Bonadona; Bernardo Bonanni; Angela R Bradbury; Carole Brewer; Bruno Buecher; Saundra 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; EMBRACE; Christoph Engel; D Gareth Evans; Lidia Feliubadaló; Lenka Foretova; Florentia Fostira; Anne-Marie Gerdes; Douglas F. Easton; Antonis C Antoniou; Jacques Simard

doi:10.1007/s10549-016-4018-2

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, Jacopo Azzollini, Banu K Arun, Anita Bane, Laure Barjhoux, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Marinus J Blok, Kristie A BobolisValérie Bonadona, Bernardo Bonanni, Angela R Bradbury, Carole Brewer, Bruno Buecher, Saundra 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, EMBRACE, Christoph Engel, D Gareth Evans, Lidia Feliubadaló, Lenka Foretova, Florentia Fostira, Anne-Marie Gerdes, Douglas F. Easton, Antonis C Antoniou, Jacques Simard

Institut for Klinisk Medicin

12 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	Breast Cancer Research and Treatment
Vol/bind	161
Udgave nummer	1
Sider (fra-til)	117-134
Antal sider	18
ISSN	0167-6806
DOI	https://doi.org/10.1007/s10549-016-4018-2
Status	Udgivet - 1 jan. 2017

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10.1007/s10549-016-4018-2Licens: CC BY

10.1007_s10549-016-4018-2Forlagets udgivne version, 1,03 MBLicens: CC BY

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Hamdi, Y., Soucy, P., Kuchenbaeker, K. B., Pastinen, T., Droit, A., Lemaçon, A., Adlard, J., Aittomäki, K., Andrulis, I. L., Arason, A., Arnold, N., Azzollini, J., Arun, B. K., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., ... Simard, J. (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, 161(1), 117-134. https://doi.org/10.1007/s10549-016-4018-2

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 et al.

I: Breast Cancer Research and Treatment, Bind 161, Nr. 1, 01.01.2017, s. 117-134.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemaçon, A, Adlard, J, Aittomäki, K, Andrulis, IL, Arason, A, Arnold, N, Azzollini, J, Arun, BK, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, KA, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, S, 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, EMBRACE, Engel, C, Gareth Evans, D, Feliubadaló, L, Foretova, L, Fostira, F, Gerdes, A-M, Easton, DF, Antoniou, AC & Simard, J 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, bind 161, nr. 1, s. 117-134. https://doi.org/10.1007/s10549-016-4018-2

Hamdi Y, Soucy P, Kuchenbaeker KB, Pastinen T, Droit A, Lemaçon A et al. 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. 2017 jan. 1;161(1):117-134. doi: 10.1007/s10549-016-4018-2

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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.",

keywords = "Journal Article",

author = "Yosr Hamdi and Penny Soucy and Kuchenbaeker, {Karoline B} and Tomi Pastinen and Arnaud Droit and Audrey Lema{\c c}on and Julian Adlard and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Adalgeir Arason and Norbert Arnold and Jacopo Azzollini and Arun, {Banu K} and Anita Bane and Laure Barjhoux and Daniel Barrowdale and Javier Benitez and Pascaline Berthet and Blok, {Marinus J} and Bobolis, {Kristie A} and Val{\'e}rie Bonadona and Bernardo Bonanni and Bradbury, {Angela R} and Carole Brewer and Bruno Buecher and Saundra Buys 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 EMBRACE and Christoph Engel and {Gareth Evans}, D and Lidia Feliubadal{\'o} and Lenka Foretova and Florentia Fostira and Anne-Marie Gerdes and Easton, {Douglas F.} and Antoniou, {Antonis C} and Jacques Simard",

year = "2017",

month = jan,

day = "1",

doi = "10.1007/s10549-016-4018-2",

language = "English",

volume = "161",

pages = "117--134",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

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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 - Azzollini, Jacopo

AU - Arun, Banu K

AU - Bane, Anita

AU - Barjhoux, Laure

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berthet, Pascaline

AU - Blok, Marinus J

AU - Bobolis, Kristie A

AU - Bonadona, Valérie

AU - Bonanni, Bernardo

AU - Bradbury, Angela R

AU - Brewer, Carole

AU - Buecher, Bruno

AU - Buys, Saundra

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 - EMBRACE

AU - Engel, Christoph

AU - Gareth Evans, D

AU - Feliubadaló, Lidia

AU - Foretova, Lenka

AU - Fostira, Florentia

AU - Gerdes, Anne-Marie

AU - Easton, Douglas F.

AU - Antoniou, Antonis C

AU - Simard, Jacques

PY - 2017/1/1

Y1 - 2017/1/1

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 - Journal Article

U2 - 10.1007/s10549-016-4018-2

DO - 10.1007/s10549-016-4018-2

M3 - Journal article

C2 - 27796716

SN - 0167-6806

VL - 161

SP - 117

EP - 134

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 1

ER -

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

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