Staff View: Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly av...

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Main Authors:	Baxter, Joseph S., Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia, Bojesen, Stig E., Brenner, Hermann, Brucker, Sara Y., Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chan, Tsun L., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L., Collaborators, Nbcs, Colonna, Sarah, Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Doerk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Engel, Christoph, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, Garcia-Closas, Montserrat, Garcia-Saenz, Jose A., Ghoussaini, Maya, Giles, Graham G., Goldberg, Mark S., Gonzalez-Neira, Anna, Guenel, Pascal, Guendert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Hou, Ming-Feng, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N., Kubelka-Sabit, Katerina, Kurian, Allison W., Kwong, Ava, Lacey, James, Lambrechts, Diether, Larson, Nicole L., Larsson, Susanna C., Le Marchand, Loic, Lejbkowicz, Flavio, Li, Jingmei, Long, Jirong, Lophatananon, Artitaya, LubiNski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Mayes, Rebecca, Menon, Usha, Milne, Roger L., Taib, Nur Aishah Mohd, Muir, Kenneth, Muranen, Taru A., Murphy, Rachel A., Nevanlinna, Heli, O'Brien, Katie M., Offit, Kenneth, Olson, Janet E., Olsson, Hakan, Park, Sue K., Park-Simon, Tjoung-Won, Patel, Alpa, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Pylkas, Katri, Rack, Brigitte, Rennert, Gad, Romero, Atocha, Ruebner, Matthias, Ruediger, Thomas, Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teo, Soo Hwang, Teras, Lauren R., Terry, Mary Beth, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, Tseng, Chiu-Chen, Untch, Michael, Vachon, Celine M., van den Ouweland, Ans M. W., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Winham, Stacey J., Winqvist, Robert, Wolk, Alicja, Wu, Anna H., Yamaji, Taiki, Zheng, Wei, Ziogas, Argyrios, Pharoah, Paul D. P., Dunning, Alison M., Easton, Douglas F., Pettitt, Stephen J., Lord, Christopher J., Haider, Syed, Orr, Nick, Fletcher, Olivia, kConFab Investigators, I, Investigators, ABCTB
Format:	Article
Published:	Cell Press 2021
Subjects:	BF Psychology QH426 Genetics
Online Access:	http://eprints.um.edu.my/34718/
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topic	BF Psychology QH426 Genetics
spellingShingle	BF Psychology QH426 Genetics Baxter, Joseph S. Johnson, Nichola Tomczyk, Katarzyna Gillespie, Andrea Maguire, Sarah Brough, Rachel Fachal, Laura Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Ahearn, Thomas U. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arndt, Volker Aronson, Kristan J. Augustinsson, Annelie Becher, Heiko Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Bogdanova, Natalia Bojesen, Stig E. Brenner, Hermann Brucker, Sara Y. Cai, Qiuyin Campa, Daniele Canzian, Federico Castelao, Jose E. Chan, Tsun L. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Choi, Ji-Yeob Clarke, Christine L. Collaborators, Nbcs Colonna, Sarah Conroy, Don M. Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. Devilee, Peter Doerk, Thilo Dossus, Laure Dwek, Miriam Eccles, Diana M. Ekici, Arif B. Eliassen, A. Heather Engel, Christoph Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Gago-Dominguez, Manuela Gao, Chi Garcia-Closas, Montserrat Garcia-Saenz, Jose A. Ghoussaini, Maya Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Guendert, Melanie Haeberle, Lothar Hahnen, Eric Haiman, Christopher A. Hall, Per Hamann, Ute Hartman, Mikael Hatse, Sigrid Hauke, Jan Hollestelle, Antoinette Hoppe, Reiner Hopper, John L. Hou, Ming-Feng Ito, Hidemi Iwasaki, Motoki Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M. Joseph, Vijai Jung, Audrey Kaaks, Rudolf Kang, Daehee Keeman, Renske Khusnutdinova, Elza Kim, Sung-Won Kosma, Veli-Matti Kraft, Peter Kristensen, Vessela N. Kubelka-Sabit, Katerina Kurian, Allison W. Kwong, Ava Lacey, James Lambrechts, Diether Larson, Nicole L. Larsson, Susanna C. Le Marchand, Loic Lejbkowicz, Flavio Li, Jingmei Long, Jirong Lophatananon, Artitaya LubiNski, Jan Mannermaa, Arto Manoochehri, Mehdi Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mavroudis, Dimitrios Mayes, Rebecca Menon, Usha Milne, Roger L. Taib, Nur Aishah Mohd Muir, Kenneth Muranen, Taru A. Murphy, Rachel A. Nevanlinna, Heli O'Brien, Katie M. Offit, Kenneth Olson, Janet E. Olsson, Hakan Park, Sue K. Park-Simon, Tjoung-Won Patel, Alpa Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Presneau, Nadege Pylkas, Katri Rack, Brigitte Rennert, Gad Romero, Atocha Ruebner, Matthias Ruediger, Thomas Saloustros, Emmanouil Sandler, Dale P. Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schneeweiss, Andreas Schoemaker, Minouk J. Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Southey, Melissa C. Stone, Jennifer Surowy, Harald Swerdlow, Anthony J. Tamimi, Rulla M. Tapper, William J. Taylor, Jack A. Teo, Soo Hwang Teras, Lauren R. Terry, Mary Beth Toland, Amanda E. Tomlinson, Ian Truong, Therese Tseng, Chiu-Chen Untch, Michael Vachon, Celine M. van den Ouweland, Ans M. W. Wang, Sophia S. Weinberg, Clarice R. Wendt, Camilla Winham, Stacey J. Winqvist, Robert Wolk, Alicja Wu, Anna H. Yamaji, Taiki Zheng, Wei Ziogas, Argyrios Pharoah, Paul D. P. Dunning, Alison M. Easton, Douglas F. Pettitt, Stephen J. Lord, Christopher J. Haider, Syed Orr, Nick Fletcher, Olivia kConFab Investigators, I Investigators, ABCTB Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
description	A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30-to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 x 10(-31)).
format	Article
author	Baxter, Joseph S. Johnson, Nichola Tomczyk, Katarzyna Gillespie, Andrea Maguire, Sarah Brough, Rachel Fachal, Laura Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Ahearn, Thomas U. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arndt, Volker Aronson, Kristan J. Augustinsson, Annelie Becher, Heiko Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Bogdanova, Natalia Bojesen, Stig E. Brenner, Hermann Brucker, Sara Y. Cai, Qiuyin Campa, Daniele Canzian, Federico Castelao, Jose E. Chan, Tsun L. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Choi, Ji-Yeob Clarke, Christine L. Collaborators, Nbcs Colonna, Sarah Conroy, Don M. Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. Devilee, Peter Doerk, Thilo Dossus, Laure Dwek, Miriam Eccles, Diana M. Ekici, Arif B. Eliassen, A. Heather Engel, Christoph Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Gago-Dominguez, Manuela Gao, Chi Garcia-Closas, Montserrat Garcia-Saenz, Jose A. Ghoussaini, Maya Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Guendert, Melanie Haeberle, Lothar Hahnen, Eric Haiman, Christopher A. Hall, Per Hamann, Ute Hartman, Mikael Hatse, Sigrid Hauke, Jan Hollestelle, Antoinette Hoppe, Reiner Hopper, John L. Hou, Ming-Feng Ito, Hidemi Iwasaki, Motoki Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M. Joseph, Vijai Jung, Audrey Kaaks, Rudolf Kang, Daehee Keeman, Renske Khusnutdinova, Elza Kim, Sung-Won Kosma, Veli-Matti Kraft, Peter Kristensen, Vessela N. Kubelka-Sabit, Katerina Kurian, Allison W. Kwong, Ava Lacey, James Lambrechts, Diether Larson, Nicole L. Larsson, Susanna C. Le Marchand, Loic Lejbkowicz, Flavio Li, Jingmei Long, Jirong Lophatananon, Artitaya LubiNski, Jan Mannermaa, Arto Manoochehri, Mehdi Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mavroudis, Dimitrios Mayes, Rebecca Menon, Usha Milne, Roger L. Taib, Nur Aishah Mohd Muir, Kenneth Muranen, Taru A. Murphy, Rachel A. Nevanlinna, Heli O'Brien, Katie M. Offit, Kenneth Olson, Janet E. Olsson, Hakan Park, Sue K. Park-Simon, Tjoung-Won Patel, Alpa Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Presneau, Nadege Pylkas, Katri Rack, Brigitte Rennert, Gad Romero, Atocha Ruebner, Matthias Ruediger, Thomas Saloustros, Emmanouil Sandler, Dale P. Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schneeweiss, Andreas Schoemaker, Minouk J. Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Southey, Melissa C. Stone, Jennifer Surowy, Harald Swerdlow, Anthony J. Tamimi, Rulla M. Tapper, William J. Taylor, Jack A. Teo, Soo Hwang Teras, Lauren R. Terry, Mary Beth Toland, Amanda E. Tomlinson, Ian Truong, Therese Tseng, Chiu-Chen Untch, Michael Vachon, Celine M. van den Ouweland, Ans M. W. Wang, Sophia S. Weinberg, Clarice R. Wendt, Camilla Winham, Stacey J. Winqvist, Robert Wolk, Alicja Wu, Anna H. Yamaji, Taiki Zheng, Wei Ziogas, Argyrios Pharoah, Paul D. P. Dunning, Alison M. Easton, Douglas F. Pettitt, Stephen J. Lord, Christopher J. Haider, Syed Orr, Nick Fletcher, Olivia kConFab Investigators, I Investigators, ABCTB
author_facet	Baxter, Joseph S. Johnson, Nichola Tomczyk, Katarzyna Gillespie, Andrea Maguire, Sarah Brough, Rachel Fachal, Laura Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Ahearn, Thomas U. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arndt, Volker Aronson, Kristan J. Augustinsson, Annelie Becher, Heiko Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Bogdanova, Natalia Bojesen, Stig E. Brenner, Hermann Brucker, Sara Y. Cai, Qiuyin Campa, Daniele Canzian, Federico Castelao, Jose E. Chan, Tsun L. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Choi, Ji-Yeob Clarke, Christine L. Collaborators, Nbcs Colonna, Sarah Conroy, Don M. Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. Devilee, Peter Doerk, Thilo Dossus, Laure Dwek, Miriam Eccles, Diana M. Ekici, Arif B. Eliassen, A. Heather Engel, Christoph Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Gago-Dominguez, Manuela Gao, Chi Garcia-Closas, Montserrat Garcia-Saenz, Jose A. Ghoussaini, Maya Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Guendert, Melanie Haeberle, Lothar Hahnen, Eric Haiman, Christopher A. Hall, Per Hamann, Ute Hartman, Mikael Hatse, Sigrid Hauke, Jan Hollestelle, Antoinette Hoppe, Reiner Hopper, John L. Hou, Ming-Feng Ito, Hidemi Iwasaki, Motoki Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M. Joseph, Vijai Jung, Audrey Kaaks, Rudolf Kang, Daehee Keeman, Renske Khusnutdinova, Elza Kim, Sung-Won Kosma, Veli-Matti Kraft, Peter Kristensen, Vessela N. Kubelka-Sabit, Katerina Kurian, Allison W. Kwong, Ava Lacey, James Lambrechts, Diether Larson, Nicole L. Larsson, Susanna C. Le Marchand, Loic Lejbkowicz, Flavio Li, Jingmei Long, Jirong Lophatananon, Artitaya LubiNski, Jan Mannermaa, Arto Manoochehri, Mehdi Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mavroudis, Dimitrios Mayes, Rebecca Menon, Usha Milne, Roger L. Taib, Nur Aishah Mohd Muir, Kenneth Muranen, Taru A. Murphy, Rachel A. Nevanlinna, Heli O'Brien, Katie M. Offit, Kenneth Olson, Janet E. Olsson, Hakan Park, Sue K. Park-Simon, Tjoung-Won Patel, Alpa Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Presneau, Nadege Pylkas, Katri Rack, Brigitte Rennert, Gad Romero, Atocha Ruebner, Matthias Ruediger, Thomas Saloustros, Emmanouil Sandler, Dale P. Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schneeweiss, Andreas Schoemaker, Minouk J. Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Southey, Melissa C. Stone, Jennifer Surowy, Harald Swerdlow, Anthony J. Tamimi, Rulla M. Tapper, William J. Taylor, Jack A. Teo, Soo Hwang Teras, Lauren R. Terry, Mary Beth Toland, Amanda E. Tomlinson, Ian Truong, Therese Tseng, Chiu-Chen Untch, Michael Vachon, Celine M. van den Ouweland, Ans M. W. Wang, Sophia S. Weinberg, Clarice R. Wendt, Camilla Winham, Stacey J. Winqvist, Robert Wolk, Alicja Wu, Anna H. Yamaji, Taiki Zheng, Wei Ziogas, Argyrios Pharoah, Paul D. P. Dunning, Alison M. Easton, Douglas F. Pettitt, Stephen J. Lord, Christopher J. Haider, Syed Orr, Nick Fletcher, Olivia kConFab Investigators, I Investigators, ABCTB
author_sort	Baxter, Joseph S.
title	Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
title_short	Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
title_full	Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
title_fullStr	Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
title_full_unstemmed	Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
title_sort	functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
publisher	Cell Press
publishDate	2021
url	http://eprints.um.edu.my/34718/
_version_	1735409621343928320
spelling	my.um.eprints.347182022-05-30T08:09:05Z http://eprints.um.edu.my/34718/ Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element Baxter, Joseph S. Johnson, Nichola Tomczyk, Katarzyna Gillespie, Andrea Maguire, Sarah Brough, Rachel Fachal, Laura Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Ahearn, Thomas U. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arndt, Volker Aronson, Kristan J. Augustinsson, Annelie Becher, Heiko Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Bogdanova, Natalia Bojesen, Stig E. Brenner, Hermann Brucker, Sara Y. Cai, Qiuyin Campa, Daniele Canzian, Federico Castelao, Jose E. Chan, Tsun L. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Choi, Ji-Yeob Clarke, Christine L. Collaborators, Nbcs Colonna, Sarah Conroy, Don M. Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. Devilee, Peter Doerk, Thilo Dossus, Laure Dwek, Miriam Eccles, Diana M. Ekici, Arif B. Eliassen, A. Heather Engel, Christoph Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Gago-Dominguez, Manuela Gao, Chi Garcia-Closas, Montserrat Garcia-Saenz, Jose A. Ghoussaini, Maya Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Guendert, Melanie Haeberle, Lothar Hahnen, Eric Haiman, Christopher A. Hall, Per Hamann, Ute Hartman, Mikael Hatse, Sigrid Hauke, Jan Hollestelle, Antoinette Hoppe, Reiner Hopper, John L. Hou, Ming-Feng Ito, Hidemi Iwasaki, Motoki Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M. Joseph, Vijai Jung, Audrey Kaaks, Rudolf Kang, Daehee Keeman, Renske Khusnutdinova, Elza Kim, Sung-Won Kosma, Veli-Matti Kraft, Peter Kristensen, Vessela N. Kubelka-Sabit, Katerina Kurian, Allison W. Kwong, Ava Lacey, James Lambrechts, Diether Larson, Nicole L. Larsson, Susanna C. Le Marchand, Loic Lejbkowicz, Flavio Li, Jingmei Long, Jirong Lophatananon, Artitaya LubiNski, Jan Mannermaa, Arto Manoochehri, Mehdi Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mavroudis, Dimitrios Mayes, Rebecca Menon, Usha Milne, Roger L. Taib, Nur Aishah Mohd Muir, Kenneth Muranen, Taru A. Murphy, Rachel A. Nevanlinna, Heli O'Brien, Katie M. Offit, Kenneth Olson, Janet E. Olsson, Hakan Park, Sue K. Park-Simon, Tjoung-Won Patel, Alpa Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Presneau, Nadege Pylkas, Katri Rack, Brigitte Rennert, Gad Romero, Atocha Ruebner, Matthias Ruediger, Thomas Saloustros, Emmanouil Sandler, Dale P. Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schneeweiss, Andreas Schoemaker, Minouk J. Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Southey, Melissa C. Stone, Jennifer Surowy, Harald Swerdlow, Anthony J. Tamimi, Rulla M. Tapper, William J. Taylor, Jack A. Teo, Soo Hwang Teras, Lauren R. Terry, Mary Beth Toland, Amanda E. Tomlinson, Ian Truong, Therese Tseng, Chiu-Chen Untch, Michael Vachon, Celine M. van den Ouweland, Ans M. W. Wang, Sophia S. Weinberg, Clarice R. Wendt, Camilla Winham, Stacey J. Winqvist, Robert Wolk, Alicja Wu, Anna H. Yamaji, Taiki Zheng, Wei Ziogas, Argyrios Pharoah, Paul D. P. Dunning, Alison M. Easton, Douglas F. Pettitt, Stephen J. Lord, Christopher J. Haider, Syed Orr, Nick Fletcher, Olivia kConFab Investigators, I Investigators, ABCTB BF Psychology QH426 Genetics A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30-to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 x 10(-31)). Cell Press 2021-07-01 Article PeerReviewed Baxter, Joseph S. and Johnson, Nichola and Tomczyk, Katarzyna and Gillespie, Andrea and Maguire, Sarah and Brough, Rachel and Fachal, Laura and Michailidou, Kyriaki and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Ahearn, Thomas U. and Andrulis, Irene L. and Anton-Culver, Hoda and Antonenkova, Natalia N. and Arndt, Volker and Aronson, Kristan J. and Augustinsson, Annelie and Becher, Heiko and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Bogdanova, Natalia and Bojesen, Stig E. and Brenner, Hermann and Brucker, Sara Y. and Cai, Qiuyin and Campa, Daniele and Canzian, Federico and Castelao, Jose E. and Chan, Tsun L. and Chang-Claude, Jenny and Chanock, Stephen J. and Chenevix-Trench, Georgia and Choi, Ji-Yeob and Clarke, Christine L. and Collaborators, Nbcs and Colonna, Sarah and Conroy, Don M. and Couch, Fergus J. and Cox, Angela and Cross, Simon S. and Czene, Kamila and Daly, Mary B. and Devilee, Peter and Doerk, Thilo and Dossus, Laure and Dwek, Miriam and Eccles, Diana M. and Ekici, Arif B. and Eliassen, A. Heather and Engel, Christoph and Fasching, Peter A. and Figueroa, Jonine and Flyger, Henrik and Gago-Dominguez, Manuela and Gao, Chi and Garcia-Closas, Montserrat and Garcia-Saenz, Jose A. and Ghoussaini, Maya and Giles, Graham G. and Goldberg, Mark S. and Gonzalez-Neira, Anna and Guenel, Pascal and Guendert, Melanie and Haeberle, Lothar and Hahnen, Eric and Haiman, Christopher A. and Hall, Per and Hamann, Ute and Hartman, Mikael and Hatse, Sigrid and Hauke, Jan and Hollestelle, Antoinette and Hoppe, Reiner and Hopper, John L. and Hou, Ming-Feng and Ito, Hidemi and Iwasaki, Motoki and Jager, Agnes and Jakubowska, Anna and Janni, Wolfgang and John, Esther M. and Joseph, Vijai and Jung, Audrey and Kaaks, Rudolf and Kang, Daehee and Keeman, Renske and Khusnutdinova, Elza and Kim, Sung-Won and Kosma, Veli-Matti and Kraft, Peter and Kristensen, Vessela N. and Kubelka-Sabit, Katerina and Kurian, Allison W. and Kwong, Ava and Lacey, James and Lambrechts, Diether and Larson, Nicole L. and Larsson, Susanna C. and Le Marchand, Loic and Lejbkowicz, Flavio and Li, Jingmei and Long, Jirong and Lophatananon, Artitaya and LubiNski, Jan and Mannermaa, Arto and Manoochehri, Mehdi and Manoukian, Siranoush and Margolin, Sara and Matsuo, Keitaro and Mavroudis, Dimitrios and Mayes, Rebecca and Menon, Usha and Milne, Roger L. and Taib, Nur Aishah Mohd and Muir, Kenneth and Muranen, Taru A. and Murphy, Rachel A. and Nevanlinna, Heli and O'Brien, Katie M. and Offit, Kenneth and Olson, Janet E. and Olsson, Hakan and Park, Sue K. and Park-Simon, Tjoung-Won and Patel, Alpa and Peterlongo, Paolo and Peto, Julian and Plaseska-Karanfilska, Dijana and Presneau, Nadege and Pylkas, Katri and Rack, Brigitte and Rennert, Gad and Romero, Atocha and Ruebner, Matthias and Ruediger, Thomas and Saloustros, Emmanouil and Sandler, Dale P. and Sawyer, Elinor J. and Schmidt, Marjanka K. and Schmutzler, Rita K. and Schneeweiss, Andreas and Schoemaker, Minouk J. and Shah, Mitul and Shen, Chen-Yang and Shu, Xiao-Ou and Simard, Jacques and Southey, Melissa C. and Stone, Jennifer and Surowy, Harald and Swerdlow, Anthony J. and Tamimi, Rulla M. and Tapper, William J. and Taylor, Jack A. and Teo, Soo Hwang and Teras, Lauren R. and Terry, Mary Beth and Toland, Amanda E. and Tomlinson, Ian and Truong, Therese and Tseng, Chiu-Chen and Untch, Michael and Vachon, Celine M. and van den Ouweland, Ans M. W. and Wang, Sophia S. and Weinberg, Clarice R. and Wendt, Camilla and Winham, Stacey J. and Winqvist, Robert and Wolk, Alicja and Wu, Anna H. and Yamaji, Taiki and Zheng, Wei and Ziogas, Argyrios and Pharoah, Paul D. P. and Dunning, Alison M. and Easton, Douglas F. and Pettitt, Stephen J. and Lord, Christopher J. and Haider, Syed and Orr, Nick and Fletcher, Olivia and kConFab Investigators, I and Investigators, ABCTB (2021) Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. American Journal of Human Genetics, 108 (7). pp. 1190-1203. ISSN 0002-9297, DOI https://doi.org/10.1016/j.ajhg.2021.05.013 <https://doi.org/10.1016/j.ajhg.2021.05.013>. 10.1016/j.ajhg.2021.05.013
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Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

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