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 Kuchenbaeker, Tomi Pastinen, Arnaud Droit, Audrey Lemaçon, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Anita L. Bane, Laure Barjhoux, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Marinus J. Blok, Kristie A. Bobolis & 152 others Valérie Bonadona, Bernardo Bonanni, Angela R. Bradbury, Carole Brewer, Bruno Buecher, Saundra S. Buys, Maria A. Caligo, Jocelyne Chiquette, Wendy K. Chung, Kathleen 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, [No Value] EMBRACE, Christoph Engel, D. Gareth Evans, Lidia Feliubadaló, Lenka Foretova, Florentia Fostira, William D. Foulkes, George Fountzilas, Eitan Friedman, Debra Frost, Pamela Ganschow, Patricia A. Ganz, Judy E. Garber, Simon A. Gayther, Study Collaborators GEMO Study Collaborators, Anne Marie Gerdes, Gord Glendon, Andrew K. Godwin, David Goldgar, Mark H. Greene, Jacek Gronwald, Eric Hahnen, Ute Hamann, Thomas v O Hansen, Steven Hart, John Hays, [No Value] HEBON, Frans B. Hogervorst, Peter J. Hulick, Evgeny Imyanitov, Claudine Isaacs, L. Izatt, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Vijai Joseph, Walter Just, Katarzyna Kaczmarek, Beth Y. Karlan, Investigators kConFab Investigators, C. M. Kets, Judy Kirk, Mieke Kriege, Yael Laitman, Maïté Laurent, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Niklas Loman, Jennifer T. Loud, Siranoush Manoukian, Milena Mariani, Sylvie Mazoyer, Lesley McGuffog, Hanne E J Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Robert L. Nussbaum, Edith Olah, Olufunmilayo I. Olopade, Kai Ren Ong, Jan C. Oosterwijk, Ana Osorio, Laura Papi, Sue K. Park, Inge Sokilde Pedersen, Bernard Gilles Peissel, Pedro Perez Segura, Paolo Peterlongo, Catherine M. Phelan, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Andrea Richardson, Mark E. Robson, Gustavo Rodriguez, M. A. Rookus, Rita K. Schmutzler, Nicolas Sevenet, Payal D. Shah, Christian F. Singer, Thomas P. Slavin, Katie M. Snape, Johanna Sokolowska, Ida Marie Heeholm Sønderstrup, Melissa Southey, Amanda B. Spurdle, Zsofia Stadler, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Yen Tan, Muy Kheng Tea, Manuel R. Teixeira, A. Teulé, Soo Hwang Teo, Mary Beth Terry, Mads Thomassen, Laima Tihomirova, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Nadine Tung, Ans M W Van Den Ouweland, Rob B. van der Luijt, Klaartje Van Engelen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Barbara Wappenschmidt, J. T. Wijnen, Timothy Rebbeck, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Silje Nord, Douglas F. Easton, Antonis C. Antoniou, Jacques Simard

Research output: Contribution to journalArticle

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
Early online dateOct 28 2016
DOIs
Publication statusPublished - Jan 2017

Fingerprint

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

  • BRCA1 and BRCA2 mutation carriers
  • Breast cancer
  • Cis-regulatory variants
  • Differential allelic expression
  • Genetic modifiers
  • Genetic susceptibility

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Azzollini, Jacopo; Bane, Anita L.; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J.; Bobolis, Kristie A.; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R.; Brewer, Carole; Buecher, Bruno; Buys, Saundra S.; Caligo, Maria A.; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen; 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; EMBRACE, [No Value]; Engel, Christoph; Gareth Evans, D.; Feliubadaló, Lidia; Foretova, Lenka; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Friedman, Eitan; Frost, Debra; Ganschow, Pamela; Ganz, Patricia A.; Garber, Judy E.; Gayther, Simon A.; GEMO Study Collaborators, Study Collaborators; Gerdes, Anne Marie; Glendon, Gord; Godwin, Andrew K.; Goldgar, David; Greene, Mark H.; Gronwald, Jacek; Hahnen, Eric; Hamann, Ute; Hansen, Thomas v O; Hart, Steven; Hays, John; HEBON, [No Value]; Hogervorst, Frans B.; Hulick, Peter J.; Imyanitov, Evgeny; Isaacs, Claudine; Izatt, L.; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Joseph, Vijai; Just, Walter; Kaczmarek, Katarzyna; Karlan, Beth Y.; kConFab Investigators, Investigators; Kets, C. M.; Kirk, Judy; Kriege, Mieke; Laitman, Yael; Laurent, Maïté; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Loman, Niklas; Loud, Jennifer T.; Manoukian, Siranoush; Mariani, Milena; Mazoyer, Sylvie; McGuffog, Lesley; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Miller, Austin; Montagna, Marco; Mulligan, Anna Marie; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nussbaum, Robert L.; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai Ren; Oosterwijk, Jan C.; Osorio, Ana; Papi, Laura; Park, Sue K.; Pedersen, Inge Sokilde; Peissel, Bernard Gilles; Segura, Pedro Perez; Peterlongo, Paolo; Phelan, Catherine M.; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark E.; Rodriguez, Gustavo; Rookus, M. A.; Schmutzler, Rita K.; Sevenet, Nicolas; Shah, Payal D.; Singer, Christian F.; Slavin, Thomas P.; Snape, Katie M.; Sokolowska, Johanna; Sønderstrup, Ida Marie Heeholm; Southey, Melissa; Spurdle, Amanda B.; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Tan, Yen; Tea, Muy Kheng; Teixeira, Manuel R.; Teulé, A.; Teo, Soo Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda E.; Tung, Nadine; Van Den Ouweland, Ans M W; van der Luijt, Rob B.; Van Engelen, Klaartje; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wijnen, J. T.; Rebbeck, Timothy; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J.; Nord, Silje; Easton, Douglas F.; Antoniou, Antonis C.; Simard, Jacques.

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, K, Pastinen, T, Droit, A, Lemaçon, A, Adlard, J, Aittomäki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, AL, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, KA, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, K, 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, NV, Engel, C, Gareth Evans, D, Feliubadaló, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, JE, Gayther, SA, GEMO Study Collaborators, SC, Gerdes, AM, Glendon, G, Godwin, AK, Goldgar, D, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, J, HEBON, NV, Hogervorst, FB, Hulick, PJ, Imyanitov, E, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, kConFab Investigators, I, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, KR, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, BG, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, ME, Rodriguez, G, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, KM, Sokolowska, J, Sønderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, MK, Teixeira, MR, Teulé, A, Teo, SH, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, Van Den Ouweland, AMW, van der Luijt, RB, Van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, 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, vol. 161, no. 1, pp. 117-134. https://doi.org/10.1007/s10549-016-4018-2
Hamdi, Yosr ; Soucy, Penny ; Kuchenbaeker, Karoline ; Pastinen, Tomi ; Droit, Arnaud ; Lemaçon, Audrey ; Adlard, Julian ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Arason, Adalgeir ; Arnold, Norbert ; Arun, Banu K. ; Azzollini, Jacopo ; Bane, Anita L. ; Barjhoux, Laure ; Barrowdale, Daniel ; Benitez, Javier ; Berthet, Pascaline ; Blok, Marinus J. ; Bobolis, Kristie A. ; Bonadona, Valérie ; Bonanni, Bernardo ; Bradbury, Angela R. ; Brewer, Carole ; Buecher, Bruno ; Buys, Saundra S. ; Caligo, Maria A. ; Chiquette, Jocelyne ; Chung, Wendy K. ; Claes, Kathleen ; 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 ; EMBRACE, [No Value] ; Engel, Christoph ; Gareth Evans, D. ; Feliubadaló, Lidia ; Foretova, Lenka ; Fostira, Florentia ; Foulkes, William D. ; Fountzilas, George ; Friedman, Eitan ; Frost, Debra ; Ganschow, Pamela ; Ganz, Patricia A. ; Garber, Judy E. ; Gayther, Simon A. ; GEMO Study Collaborators, Study Collaborators ; Gerdes, Anne Marie ; Glendon, Gord ; Godwin, Andrew K. ; Goldgar, David ; Greene, Mark H. ; Gronwald, Jacek ; Hahnen, Eric ; Hamann, Ute ; Hansen, Thomas v O ; Hart, Steven ; Hays, John ; HEBON, [No Value] ; Hogervorst, Frans B. ; Hulick, Peter J. ; Imyanitov, Evgeny ; Isaacs, Claudine ; Izatt, L. ; Jakubowska, Anna ; James, Paul A. ; Janavicius, Ramunas ; Jensen, Uffe Birk ; John, Esther M. ; Joseph, Vijai ; Just, Walter ; Kaczmarek, Katarzyna ; Karlan, Beth Y. ; kConFab Investigators, Investigators ; Kets, C. M. ; Kirk, Judy ; Kriege, Mieke ; Laitman, Yael ; Laurent, Maïté ; Lazaro, Conxi ; Leslie, Goska ; Lester, Jenny ; Lesueur, Fabienne ; Liljegren, Annelie ; Loman, Niklas ; Loud, Jennifer T. ; Manoukian, Siranoush ; Mariani, Milena ; Mazoyer, Sylvie ; McGuffog, Lesley ; Meijers-Heijboer, Hanne E J ; Meindl, Alfons ; Miller, Austin ; Montagna, Marco ; Mulligan, Anna Marie ; Nathanson, Katherine L. ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Nussbaum, Robert L. ; Olah, Edith ; Olopade, Olufunmilayo I. ; Ong, Kai Ren ; Oosterwijk, Jan C. ; Osorio, Ana ; Papi, Laura ; Park, Sue K. ; Pedersen, Inge Sokilde ; Peissel, Bernard Gilles ; Segura, Pedro Perez ; Peterlongo, Paolo ; Phelan, Catherine M. ; Radice, Paolo ; Rantala, Johanna ; Rappaport-Fuerhauser, Christine ; Rennert, Gad ; Richardson, Andrea ; Robson, Mark E. ; Rodriguez, Gustavo ; Rookus, M. A. ; Schmutzler, Rita K. ; Sevenet, Nicolas ; Shah, Payal D. ; Singer, Christian F. ; Slavin, Thomas P. ; Snape, Katie M. ; Sokolowska, Johanna ; Sønderstrup, Ida Marie Heeholm ; Southey, Melissa ; Spurdle, Amanda B. ; Stadler, Zsofia ; Stoppa-Lyonnet, Dominique ; Sukiennicki, Grzegorz ; Sutter, Christian ; Tan, Yen ; Tea, Muy Kheng ; Teixeira, Manuel R. ; Teulé, A. ; Teo, Soo Hwang ; Terry, Mary Beth ; Thomassen, Mads ; Tihomirova, Laima ; Tischkowitz, Marc ; Tognazzo, Silvia ; Toland, Amanda E. ; Tung, Nadine ; Van Den Ouweland, Ans M W ; van der Luijt, Rob B. ; Van Engelen, Klaartje ; van Rensburg, Elizabeth J. ; Varon-Mateeva, Raymonda ; Wappenschmidt, Barbara ; Wijnen, J. T. ; Rebbeck, Timothy ; Chenevix-Trench, Georgia ; Offit, Kenneth ; Couch, Fergus J. ; Nord, Silje ; Easton, Douglas F. ; Antoniou, Antonis C. ; Simard, Jacques. / 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.
@article{f05ee62ee2da401f9e0a42f9d133a32d,
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 = "BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility",
author = "Yosr Hamdi and Penny Soucy and Karoline Kuchenbaeker 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 Bane, {Anita L.} 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 Buys, {Saundra S.} and Caligo, {Maria A.} and Jocelyne Chiquette and Chung, {Wendy K.} and Kathleen Claes 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, {[No Value]} and Christoph Engel and {Gareth Evans}, D. and Lidia Feliubadal{\'o} and Lenka Foretova and Florentia Fostira and Foulkes, {William D.} and George Fountzilas and Eitan Friedman and Debra Frost and Pamela Ganschow and Ganz, {Patricia A.} and Garber, {Judy E.} and Gayther, {Simon A.} and {GEMO Study Collaborators}, {Study Collaborators} and Gerdes, {Anne Marie} and Gord Glendon and Godwin, {Andrew K.} and David Goldgar and Greene, {Mark H.} and Jacek Gronwald and Eric Hahnen and Ute Hamann and Hansen, {Thomas v O} and Steven Hart and John Hays and HEBON, {[No Value]} and Hogervorst, {Frans B.} and Hulick, {Peter J.} and Evgeny Imyanitov and Claudine Isaacs and L. Izatt and Anna Jakubowska and James, {Paul A.} and Ramunas Janavicius and Jensen, {Uffe Birk} and John, {Esther M.} and Vijai Joseph and Walter Just and Katarzyna Kaczmarek and Karlan, {Beth Y.} and {kConFab Investigators}, Investigators and Kets, {C. M.} and Judy Kirk and Mieke Kriege and Yael Laitman and Ma{\"i}t{\'e} Laurent and Conxi Lazaro and Goska Leslie and Jenny Lester and Fabienne Lesueur and Annelie Liljegren and Niklas Loman and Loud, {Jennifer T.} and Siranoush Manoukian and Milena Mariani and Sylvie Mazoyer and Lesley McGuffog and Meijers-Heijboer, {Hanne E J} and Alfons Meindl and Austin Miller and Marco Montagna and Mulligan, {Anna Marie} and Nathanson, {Katherine L.} and Neuhausen, {Susan L.} and Heli Nevanlinna and Nussbaum, {Robert L.} and Edith Olah and Olopade, {Olufunmilayo I.} and Ong, {Kai Ren} and Oosterwijk, {Jan C.} and Ana Osorio and Laura Papi and Park, {Sue K.} and Pedersen, {Inge Sokilde} and Peissel, {Bernard Gilles} and Segura, {Pedro Perez} and Paolo Peterlongo and Phelan, {Catherine M.} and Paolo Radice and Johanna Rantala and Christine Rappaport-Fuerhauser and Gad Rennert and Andrea Richardson and Robson, {Mark E.} and Gustavo Rodriguez and Rookus, {M. A.} and Schmutzler, {Rita K.} and Nicolas Sevenet and Shah, {Payal D.} and Singer, {Christian F.} and Slavin, {Thomas P.} and Snape, {Katie M.} and Johanna Sokolowska and S{\o}nderstrup, {Ida Marie Heeholm} and Melissa Southey and Spurdle, {Amanda B.} and Zsofia Stadler and Dominique Stoppa-Lyonnet and Grzegorz Sukiennicki and Christian Sutter and Yen Tan and Tea, {Muy Kheng} and Teixeira, {Manuel R.} and A. Teul{\'e} and Teo, {Soo Hwang} and Terry, {Mary Beth} and Mads Thomassen and Laima Tihomirova and Marc Tischkowitz and Silvia Tognazzo and Toland, {Amanda E.} and Nadine Tung and {Van Den Ouweland}, {Ans M W} and {van der Luijt}, {Rob B.} and {Van Engelen}, Klaartje and {van Rensburg}, {Elizabeth J.} and Raymonda Varon-Mateeva and Barbara Wappenschmidt and Wijnen, {J. T.} and Timothy Rebbeck and Georgia Chenevix-Trench and Kenneth Offit and Couch, {Fergus J.} and Silje Nord and Easton, {Douglas F.} and Antoniou, {Antonis C.} and Jacques Simard",
year = "2017",
month = "1",
doi = "10.1007/s10549-016-4018-2",
language = "English",
volume = "161",
pages = "117--134",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York LLC",
number = "1",

}

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

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 L.

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 S.

AU - Caligo, Maria A.

AU - Chiquette, Jocelyne

AU - Chung, Wendy K.

AU - Claes, Kathleen

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, [No Value]

AU - Engel, Christoph

AU - Gareth Evans, D.

AU - Feliubadaló, Lidia

AU - Foretova, Lenka

AU - Fostira, Florentia

AU - Foulkes, William D.

AU - Fountzilas, George

AU - Friedman, Eitan

AU - Frost, Debra

AU - Ganschow, Pamela

AU - Ganz, Patricia A.

AU - Garber, Judy E.

AU - Gayther, Simon A.

AU - GEMO Study Collaborators, Study Collaborators

AU - Gerdes, Anne Marie

AU - Glendon, Gord

AU - Godwin, Andrew K.

AU - Goldgar, David

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Hahnen, Eric

AU - Hamann, Ute

AU - Hansen, Thomas v O

AU - Hart, Steven

AU - Hays, John

AU - HEBON, [No Value]

AU - Hogervorst, Frans B.

AU - Hulick, Peter J.

AU - Imyanitov, Evgeny

AU - Isaacs, Claudine

AU - Izatt, L.

AU - Jakubowska, Anna

AU - James, Paul A.

AU - Janavicius, Ramunas

AU - Jensen, Uffe Birk

AU - John, Esther M.

AU - Joseph, Vijai

AU - Just, Walter

AU - Kaczmarek, Katarzyna

AU - Karlan, Beth Y.

AU - kConFab Investigators, Investigators

AU - Kets, C. M.

AU - Kirk, Judy

AU - Kriege, Mieke

AU - Laitman, Yael

AU - Laurent, Maïté

AU - Lazaro, Conxi

AU - Leslie, Goska

AU - Lester, Jenny

AU - Lesueur, Fabienne

AU - Liljegren, Annelie

AU - Loman, Niklas

AU - Loud, Jennifer T.

AU - Manoukian, Siranoush

AU - Mariani, Milena

AU - Mazoyer, Sylvie

AU - McGuffog, Lesley

AU - Meijers-Heijboer, Hanne E J

AU - Meindl, Alfons

AU - Miller, Austin

AU - Montagna, Marco

AU - Mulligan, Anna Marie

AU - Nathanson, Katherine L.

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Nussbaum, Robert L.

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Ong, Kai Ren

AU - Oosterwijk, Jan C.

AU - Osorio, Ana

AU - Papi, Laura

AU - Park, Sue K.

AU - Pedersen, Inge Sokilde

AU - Peissel, Bernard Gilles

AU - Segura, Pedro Perez

AU - Peterlongo, Paolo

AU - Phelan, Catherine M.

AU - Radice, Paolo

AU - Rantala, Johanna

AU - Rappaport-Fuerhauser, Christine

AU - Rennert, Gad

AU - Richardson, Andrea

AU - Robson, Mark E.

AU - Rodriguez, Gustavo

AU - Rookus, M. A.

AU - Schmutzler, Rita K.

AU - Sevenet, Nicolas

AU - Shah, Payal D.

AU - Singer, Christian F.

AU - Slavin, Thomas P.

AU - Snape, Katie M.

AU - Sokolowska, Johanna

AU - Sønderstrup, Ida Marie Heeholm

AU - Southey, Melissa

AU - Spurdle, Amanda B.

AU - Stadler, Zsofia

AU - Stoppa-Lyonnet, Dominique

AU - Sukiennicki, Grzegorz

AU - Sutter, Christian

AU - Tan, Yen

AU - Tea, Muy Kheng

AU - Teixeira, Manuel R.

AU - Teulé, A.

AU - Teo, Soo Hwang

AU - Terry, Mary Beth

AU - Thomassen, Mads

AU - Tihomirova, Laima

AU - Tischkowitz, Marc

AU - Tognazzo, Silvia

AU - Toland, Amanda E.

AU - Tung, Nadine

AU - Van Den Ouweland, Ans M W

AU - van der Luijt, Rob B.

AU - Van Engelen, Klaartje

AU - van Rensburg, Elizabeth J.

AU - Varon-Mateeva, Raymonda

AU - Wappenschmidt, Barbara

AU - Wijnen, J. T.

AU - Rebbeck, Timothy

AU - Chenevix-Trench, Georgia

AU - Offit, Kenneth

AU - Couch, Fergus J.

AU - Nord, Silje

AU - Easton, Douglas F.

AU - Antoniou, Antonis C.

AU - Simard, Jacques

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 - BRCA1 and BRCA2 mutation carriers

KW - Breast cancer

KW - Cis-regulatory variants

KW - Differential allelic expression

KW - Genetic modifiers

KW - Genetic susceptibility

UR - http://www.scopus.com/inward/record.url?scp=84992735226&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992735226&partnerID=8YFLogxK

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 -