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

EMBRACE; GEMO Study Collaborators; HEBON; KConFab Investigators; Lenka Foretova; Florentia Fostira; William D. Foulkes; George Fountzilas; Eitan Friedman; Debra Frost; Pamela Ganschow; Patricia A. Ganz; Judy Garber; Simon A. Gayther; Anne-Marie Gerdes; Gord Glendon; Andrew K. Godwin; David E. Goldgar; Mark H. Greene; Jacek Gronwald; Eric Hahnen; Ute Hamann; Thomas V. O. Hansen; Steven Hart; John L. Hays; Frans B. L. Hogervorst; Peter J. Hulick; Evgeny N. Imyanitov; Claudine Isaacs; Louise Izatt; Anna Jakubowska; Paul James; Ramunas Janavicius; Uffe Birk Jensen; Esther M. John; Vijai Joseph; Walter Just; Katarzyna Kaczmarek; Beth Y. Karlan; Carolien 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; 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; Ana Osorio; Laura Papi; Sue Kyung Park; Inge Sokilde Pedersen; Bernard Peissel; Pedro Perez Segura; Paolo Peterlongo; Catherine M. Phelan; Paolo Radice; Johanna Rantala; Christine Rappaport-Fuerhauser; Gad Rennert; Andrea Richardson; Mark Robson; Gustavo C. Rodriguez; Matti A. Rookus; Rita Katharina Schmutzler; Nicolas Sevenet; Payal D. Shah; Christian F. Singer; Thomas P. Slavin; Katie 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; Alex Teulé; Soo-Hwang teo; Mary Beth Terry; Mads Thomassen; Laima Tihomirova; Marc Tischkowitz; Silvia Tognazzo; Amanda Ewart Toland; Nadine Tung; Ans M. W. van den Ouweland; Rob B. van der Luijt; Elizabeth J. van Rensburg; Raymonda Varon-Mateeva; Barbara Wappenschmidt; Juul T. Wijnen; Timothy Rebbeck; Georgia Chenevix-Trench; Kenneth Offit; Fergus J. Couch; Silje Nord; Douglas F. Easton; Antonis C. Antoniou; Jacques Simard

doi: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

EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Lenka Foretova, Florentia Fostira, William D. Foulkes, George Fountzilas, Eitan Friedman, Debra Frost, Pamela Ganschow, Patricia A. Ganz, Judy Garber, Simon A. Gayther, Anne-Marie Gerdes, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Jacek GronwaldEric Hahnen, Ute Hamann, Thomas V. O. Hansen, Steven Hart, John L. Hays, Frans B. L. Hogervorst, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Vijai Joseph, Walter Just, Katarzyna Kaczmarek, Beth Y. Karlan, Carolien 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, 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, Ana Osorio, Laura Papi, Sue Kyung Park, Inge Sokilde Pedersen, Bernard Peissel, Pedro Perez Segura, Paolo Peterlongo, Catherine M. Phelan, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Andrea Richardson, Mark Robson, Gustavo C. Rodriguez, Matti A. Rookus, Rita Katharina Schmutzler, Nicolas Sevenet, Payal D. Shah, Christian F. Singer, Thomas P. Slavin, Katie 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, Alex Teulé, Soo-Hwang teo, Mary Beth Terry, Mads Thomassen, Laima Tihomirova, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Nadine Tung, Ans M. W. van den Ouweland, Rob B. van der Luijt, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Juul 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 journal › Article › Academic › peer-review

19 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 language	English
Pages (from-to)	117-134
Number of pages	18
Journal	Breast cancer research and treatment
Volume	161
Issue number	1
Early online date	2016
DOIs	https://doi.org/10.1007/s10549-016-4018-2
Publication status	Published - 1 Jan 2017

Keywords

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

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https://doi.org/10.1007/s10549-016-4018-2

Cite this

EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Foretova, L., Fostira, F., Foulkes, W. D., Fountzilas, G., Friedman, E., Frost, D., Ganschow, P., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A.-M., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., ... 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

@article{2e41994e6a514f5aab02150920647a32,

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 = "EMBRACE and {GEMO Study Collaborators} and HEBON and {KConFab Investigators} and 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 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 {Gareth Evans}, D. and Lidia Feliubadalo and Meijers-Heijboer, {Hanne E.J.} and Oosterwijk, {Jan C.} and {van Engelen}, Klaartje 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 Judy Garber and Gayther, {Simon A.} and Anne-Marie Gerdes and Gord Glendon and Godwin, {Andrew K.} and Goldgar, {David E.} and Greene, {Mark H.} and Jacek Gronwald and Eric Hahnen and Ute Hamann and Hansen, {Thomas V. O.} and Steven Hart and Hays, {John L.} and Hogervorst, {Frans B. L.} and Hulick, {Peter J.} and Imyanitov, {Evgeny N.} and Claudine Isaacs and Louise Izatt and Anna Jakubowska and Paul James 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 Kets, {Carolien 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 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 Kai-Ren Ong and Ana Osorio and Laura Papi and Park, {Sue Kyung} and Pedersen, {Inge Sokilde} and Bernard Peissel 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 Mark Robson and Rodriguez, {Gustavo C.} and Rookus, {Matti A.} and Schmutzler, {Rita Katharina} and Nicolas Sevenet and Shah, {Payal D.} and Singer, {Christian F.} and Slavin, {Thomas P.} and Katie Snape 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 Muy-Kheng tea and Teixeira, {Manuel R.} and Alex Teul{\'e} and Soo-Hwang teo and Terry, {Mary Beth} and Mads Thomassen and Laima Tihomirova and Marc Tischkowitz and Silvia Tognazzo and Toland, {Amanda Ewart} and Nadine Tung and {van den Ouweland}, {Ans M. W.} and {van der Luijt}, {Rob B.} and {van Rensburg}, {Elizabeth J.} and Raymonda Varon-Mateeva and Barbara Wappenschmidt and Wijnen, {Juul 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 = jan,

day = "1",

doi = "https://doi.org/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",

number = "1",

}

EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, 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, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sønderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, tea, M-K, Teixeira, MR, Teulé, A, teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, 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

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. / EMBRACE; GEMO Study Collaborators; HEBON et al.
In: Breast cancer research and treatment, Vol. 161, No. 1, 01.01.2017, p. 117-134.

Research output: Contribution to journal › Article › Academic › peer-review

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 - EMBRACE

AU - GEMO Study Collaborators

AU - HEBON

AU - KConFab Investigators

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 - Gareth Evans, D.

AU - Feliubadalo, Lidia

AU - Meijers-Heijboer, Hanne E.J.

AU - Oosterwijk, Jan C.

AU - van Engelen, Klaartje

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

AU - Gayther, Simon A.

AU - Gerdes, Anne-Marie

AU - Glendon, Gord

AU - Godwin, Andrew K.

AU - Goldgar, David E.

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Hahnen, Eric

AU - Hamann, Ute

AU - Hansen, Thomas V. O.

AU - Hart, Steven

AU - Hays, John L.

AU - Hogervorst, Frans B. L.

AU - Hulick, Peter J.

AU - Imyanitov, Evgeny N.

AU - Isaacs, Claudine

AU - Izatt, Louise

AU - Jakubowska, Anna

AU - James, Paul

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 - Kets, Carolien 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 - 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 - Osorio, Ana

AU - Papi, Laura

AU - Park, Sue Kyung

AU - Pedersen, Inge Sokilde

AU - Peissel, Bernard

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

AU - Rodriguez, Gustavo C.

AU - Rookus, Matti A.

AU - Schmutzler, Rita Katharina

AU - Sevenet, Nicolas

AU - Shah, Payal D.

AU - Singer, Christian F.

AU - Slavin, Thomas P.

AU - Snape, Katie

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, Alex

AU - teo, Soo-Hwang

AU - Terry, Mary Beth

AU - Thomassen, Mads

AU - Tihomirova, Laima

AU - Tischkowitz, Marc

AU - Tognazzo, Silvia

AU - Toland, Amanda Ewart

AU - Tung, Nadine

AU - van den Ouweland, Ans M. W.

AU - van der Luijt, Rob B.

AU - van Rensburg, Elizabeth J.

AU - Varon-Mateeva, Raymonda

AU - Wappenschmidt, Barbara

AU - Wijnen, Juul 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 - 2017/1/1

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 - 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

U2 - https://doi.org/10.1007/s10549-016-4018-2

DO - https://doi.org/10.1007/s10549-016-4018-2

M3 - 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 -

EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Foretova L, Fostira F 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. Epub 2016. doi: 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

Abstract

Keywords

Access to Document

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Cite this