Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

Glubb, Dylan, Maranian, Mel J., Michailidou, Kyriaki, Pooley, Karen A., Meyer, Kerstin, Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A., Hillman, Kristine M., Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L., Southey, Melissa C., Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., van der Schoot, C. Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter, Ruebner, Matthias, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul D. P., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Ronxi, Surowy, Harald, Guenel, Pascal, Truong, Therese, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E., Nordestgaard, Borge, Nielsen, Sune, Flyger, Henrik, Gonzalez-Neira, Anna, Benitez, Javier, Zamora, M. Pilar, Arias Perez, Jose Ignacio, Anton-Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Ko, Yon-Dschun, Bruning, Thomas, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Dork, Thilo, Bogdanova, Natalia V., Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Wu, Anna H., Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O., Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Radice, Paolo, Peterlongo, Paolo, Barile, Monica, Capra, Fabio, Couch, Fergus J., Olson, Janet E., Hallberg, Emily, Vachon, Celine, Giles, Graham G., Milne, Roger L., McLean, Catriona McLean, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, LeMarchand, Loic Le, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Teo, Soo Hwang, Yip, Cheng Har, See, Mee-Hoong, Cornes, Belinda, Cheng, Ching-Yu, Ikram, M. Kamram, Kristensen, Vessela, Zheng, Wei, Halverson, Sandra L., Shrubsole, Martha, Long, Jirong, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Klevebring, Daniel, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W. M., Collee, J. Margriet, Hall, Per, Li, Jingmei, Humphreys, Keith, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Hui, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Blot, William, Signorello, Lisa B., Cai, Qiuyin, Shah, Mitul, Ghoussaini, Maya, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Tang, Anthony, Hamann, Ute, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Olswold, Curtis, Slager, Susan, Toland, Amanda E., Yannoukakos, Drakoulis, Shen, Chen-Yang, Wu, Pei-Ei, Yu, Jyh-Cherng, Hou, Ming-Feng, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Pita, Guillermo, Alonso, M. Rosario, Alvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Ahmed, Shahana, Healey, Catherine S., Brown, Melissa A., Ponder, Bruce A. J., Chenevix-Trench, Georgia, Thompson, Deborah J., Edwards, Stacey L., Easton, Douglas F., Dunning, Alison M. and French, Juliet D. (2015) Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. American Journal of Human Genetics, 96 1: 5-20. doi:10.1016/j.ajhg.2014.11.009


Author Glubb, Dylan
Maranian, Mel J.
Michailidou, Kyriaki
Pooley, Karen A.
Meyer, Kerstin
Kar, Siddhartha
Carlebur, Saskia
O'Reilly, Martin
Betts, Joshua A.
Hillman, Kristine M.
Kaufmann, Susanne
Beesley, Jonathan
Canisius, Sander
Hopper, John L.
Southey, Melissa C.
Tsimiklis, Helen
Apicella, Carmel
Schmidt, Marjanka K.
Broeks, Annegien
Hogervorst, Frans B.
van der Schoot, C. Ellen
Muir, Kenneth
Lophatananon, Artitaya
Stewart-Brown, Sarah
Siriwanarangsan, Pornthep
Fasching, Peter
Ruebner, Matthias
Ekici, Arif B.
Beckmann, Matthias W.
Peto, Julian
dos-Santos-Silva, Isabel
Fletcher, Olivia
Johnson, Nichola
Pharoah, Paul D. P.
Bolla, Manjeet K.
Wang, Qin
Dennis, Joe
Sawyer, Elinor J.
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Burwinkel, Barbara
Marme, Frederik
Yang, Ronxi
Surowy, Harald
Guenel, Pascal
Truong, Therese
Menegaux, Florence
Sanchez, Marie
Bojesen, Stig E.
Nordestgaard, Borge
Nielsen, Sune
Flyger, Henrik
Gonzalez-Neira, Anna
Benitez, Javier
Zamora, M. Pilar
Arias Perez, Jose Ignacio
Anton-Culver, Hoda
Neuhausen, Susan L.
Brenner, Hermann
Dieffenbach, Aida Karina
Arndt, Volker
Stegmaier, Christa
Meindl, Alfons
Schmutzler, Rita K.
Brauch, Hiltrud
Ko, Yon-Dschun
Bruning, Thomas
Nevanlinna, Heli
Muranen, Taru A.
Aittomaki, Kristiina
Blomqvist, Carl
Matsuo, Keitaro
Ito, Hidemi
Iwata, Hiroji
Tanaka, Hideo
Dork, Thilo
Bogdanova, Natalia V.
Helbig, Sonja
Lindblom, Annika
Margolin, Sara
Mannermaa, Arto
Kataja, Vesa
Kosma, Veli-Matti
Hartikainen, Jaana M.
Wu, Anna H.
Tseng, Chiu-chen
Van Den Berg, David
Stram, Daniel O.
Lambrechts, Diether
Zhao, Hui
Weltens, Caroline
van Limbergen, Erik
Chang-Claude, Jenny
Flesch-Janys, Dieter
Rudolph, Anja
Seibold, Petra
Radice, Paolo
Peterlongo, Paolo
Barile, Monica
Capra, Fabio
Couch, Fergus J.
Olson, Janet E.
Hallberg, Emily
Vachon, Celine
Giles, Graham G.
Milne, Roger L.
McLean, Catriona McLean
Haiman, Christopher A.
Henderson, Brian E.
Schumacher, Fredrick
LeMarchand, Loic Le
Simard, Jacques
Goldberg, Mark S.
Labreche, France
Dumont, Martine
Teo, Soo Hwang
Yip, Cheng Har
See, Mee-Hoong
Cornes, Belinda
Cheng, Ching-Yu
Ikram, M. Kamram
Kristensen, Vessela
Zheng, Wei
Halverson, Sandra L.
Shrubsole, Martha
Long, Jirong
Winqvist, Robert
Pylkas, Katri
Jukkola-Vuorinen, Arja
Kauppila, Saila
Andrulis, Irene L.
Knight, Julia A.
Glendon, Gord
Tchatchou, Sandrine
Devilee, Peter
Tollenaar, Robert A. E. M.
Seynaeve, Caroline
Van Asperen, Christi J.
Garcia-Closas, Montserrat
Figueroa, Jonine
Chanock, Stephen J.
Lissowska, Jolanta
Czene, Kamila
Klevebring, Daniel
Darabi, Hatef
Eriksson, Mikael
Hooning, Maartje J.
Hollestelle, Antoinette
Martens, John W. M.
Collee, J. Margriet
Hall, Per
Li, Jingmei
Humphreys, Keith
Shu, Xiao-Ou
Lu, Wei
Gao, Yu-Tang
Cai, Hui
Cox, Angela
Cross, Simon S.
Reed, Malcolm W. R.
Blot, William
Signorello, Lisa B.
Cai, Qiuyin
Shah, Mitul
Ghoussaini, Maya
Kang, Daehee
Choi, Ji-Yeob
Park, Sue K.
Noh, Dong-Young
Hartman, Mikael
Miao, Hui
Lim, Wei Yen
Tang, Anthony
Hamann, Ute
Torres, Diana
Jakubowska, Anna
Lubinski, Jan
Jaworska, Katarzyna
Durda, Katarzyna
Sangrajrang, Suleeporn
Gaborieau, Valerie
Brennan, Paul
McKay, James
Olswold, Curtis
Slager, Susan
Toland, Amanda E.
Yannoukakos, Drakoulis
Shen, Chen-Yang
Wu, Pei-Ei
Yu, Jyh-Cherng
Hou, Ming-Feng
Swerdlow, Anthony
Ashworth, Alan
Orr, Nick
Jones, Michael
Pita, Guillermo
Alonso, M. Rosario
Alvarez, Nuria
Herrero, Daniel
Tessier, Daniel C.
Vincent, Daniel
Bacot, Francois
Luccarini, Craig
Baynes, Caroline
Ahmed, Shahana
Healey, Catherine S.
Brown, Melissa A.
Ponder, Bruce A. J.
Chenevix-Trench, Georgia
Thompson, Deborah J.
Edwards, Stacey L.
Easton, Douglas F.
Dunning, Alison M.
French, Juliet D.
Title Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1
Formatted title
Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
0002-9297
Publication date 2015-01-08
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2014.11.009
Open Access Status DOI
Volume 96
Issue 1
Start page 5
End page 20
Total pages 16
Place of publication Cambridge, MA United States
Publisher Cell Press [Elsevier]
Collection year 2015
Language eng
Formatted abstract
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21–1.27, ptrend = 5.7 × 10−44) and estrogen-receptor-negative (ER: OR = 1.10, 95% CI = 1.05–1.15, ptrend = 3.0 × 10−4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10−5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87–0.93, pcond = 1.4 × 10−4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 8 Jan 2015

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
School of Medicine Publications
 
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