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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5-20 |
| Number of pages | 16 |
| Journal | American Journal of Human Genetics |
| Volume | 96 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 8 2015 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. / Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; 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 A.; 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, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-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; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, 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; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee Hoong; Cornes, Belinda; Cheng, Ching Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, 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.; García-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; Collée, 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; Álvarez, 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.
In: American Journal of Human Genetics, Vol. 96, No. 1, 08.01.2015, p. 5-20.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1
AU - Glubb, Dylan M.
AU - Maranian, Mel J.
AU - Michailidou, Kyriaki
AU - Pooley, Karen A.
AU - Meyer, Kerstin B.
AU - Kar, Siddhartha
AU - Carlebur, Saskia
AU - O'Reilly, Martin
AU - Betts, Joshua A.
AU - Hillman, Kristine M.
AU - Kaufmann, Susanne
AU - Beesley, Jonathan
AU - Canisius, Sander
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Tsimiklis, Helen
AU - Apicella, Carmel
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Hogervorst, Frans B.
AU - Van Der Schoot, C. Ellen
AU - Muir, Kenneth
AU - Lophatananon, Artitaya
AU - Stewart-Brown, Sarah
AU - Siriwanarangsan, Pornthep
AU - Fasching, Peter A.
AU - Ruebner, Matthias
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Peto, Julian
AU - Dos-Santos-Silva, Isabel
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - Pharoah, Paul D P
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dennis, Joe
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Yang, Rongxi
AU - Surowy, Harald
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - González-Neira, Anna
AU - Benitez, Javier
AU - Zamora, M. Pilar
AU - Arias Perez, Jose Ignacio
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Meindl, Alfons
AU - Schmutzler, Rita K.
AU - Brauch, Hiltrud
AU - Ko, Yon Dschun
AU - Brüning, Thomas
AU - Nevanlinna, Heli
AU - Muranen, Taru A.
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Matsuo, Keitaro
AU - Ito, Hidemi
AU - Iwata, Hiroji
AU - Tanaka, Hideo
AU - Dörk, Thilo
AU - Bogdanova, Natalia V.
AU - Helbig, Sonja
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Wu, Anna H.
AU - Tseng, Chiu Chen
AU - Van Den Berg, David
AU - Stram, Daniel O.
AU - Lambrechts, Diether
AU - Zhao, Hui
AU - Weltens, Caroline
AU - Van Limbergen, Erik
AU - Chang-Claude, Jenny
AU - Flesch-Janys, Dieter
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Barile, Monica
AU - Capra, Fabio
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Hallberg, Emily
AU - Vachon, Celine
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - McLean, Catriona
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Schumacher, Fredrick
AU - Le Marchand, Loic
AU - Simard, Jacques
AU - Goldberg, Mark S.
AU - Labrèche, France
AU - Dumont, Martine
AU - Teo, Soo Hwang
AU - Yip, Cheng Har
AU - See, Mee Hoong
AU - Cornes, Belinda
AU - Cheng, Ching Yu
AU - Ikram, M. Kamran
AU - Kristensen, Vessela
AU - Zheng, Wei
AU - Halverson, Sandra L.
AU - Shrubsole, Martha
AU - Long, Jirong
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Kauppila, Saila
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Glendon, Gord
AU - Tchatchou, Sandrine
AU - Devilee, Peter
AU - Tollenaar, Robert A E M
AU - Seynaeve, Caroline
AU - Van Asperen, Christi J.
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Chanock, Stephen J.
AU - Lissowska, Jolanta
AU - Czene, Kamila
AU - Klevebring, Daniel
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Hooning, Maartje J.
AU - Hollestelle, Antoinette
AU - Martens, John W M
AU - Collée, J. Margriet
AU - Hall, Per
AU - Li, Jingmei
AU - Humphreys, Keith
AU - Shu, Xiao Ou
AU - Lu, Wei
AU - Gao, Yu Tang
AU - Cai, Hui
AU - Cox, Angela
AU - Cross, Simon S.
AU - Reed, Malcolm W R
AU - Blot, William
AU - Signorello, Lisa B.
AU - Cai, Qiuyin
AU - Shah, Mitul
AU - Ghoussaini, Maya
AU - Kang, Daehee
AU - Choi, Ji Yeob
AU - Park, Sue K.
AU - Noh, Dong Young
AU - Hartman, Mikael
AU - Miao, Hui
AU - Lim, Wei Yen
AU - Tang, Anthony
AU - Hamann, Ute
AU - Torres, Diana
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska, Katarzyna
AU - Durda, Katarzyna
AU - Sangrajrang, Suleeporn
AU - Gaborieau, Valerie
AU - Brennan, Paul
AU - McKay, James
AU - Olswold, Curtis
AU - Slager, Susan
AU - Toland, Amanda E.
AU - Yannoukakos, Drakoulis
AU - Shen, Chen Yang
AU - Wu, Pei Ei
AU - Yu, Jyh Cherng
AU - Hou, Ming Feng
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nick
AU - Jones, Michael
AU - Pita, Guillermo
AU - Alonso, M. Rosario
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francois
AU - Luccarini, Craig
AU - Baynes, Caroline
AU - Ahmed, Shahana
AU - Healey, Catherine S.
AU - Brown, Melissa A.
AU - Ponder, Bruce A J
AU - Chenevix-Trench, Georgia
AU - Thompson, Deborah J.
AU - Edwards, Stacey L.
AU - Easton, Douglas F.
AU - Dunning, Alison M.
AU - French, Juliet D.
PY - 2015/1/8
Y1 - 2015/1/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84920818376&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920818376&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.11.009
DO - 10.1016/j.ajhg.2014.11.009
M3 - Article
VL - 96
SP - 5
EP - 20
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -