Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation
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Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. / Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Milne, Roger L; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M Rosario; Pita, Guillermo; Neuhausen, Susan L; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; van den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham; Haiman, Christopher A; Le Marchand, Loic; Goldberg, Mark S; Teo, Soo-Hwang; Yip, Cheng Har; Borresen-Dale, Anne-Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Koppert, Linetta B; Li, Jingmei; Shu, Xiao-Ou; Zheng, Ying; Cox, Angela; Cross, Simon S; Shah, Mitul; Rhenius, Valerie; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Schoemaker, Minouk J; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F; Dunning, Alison M; Edwards, Stacey L; kConFab/AOCS Investigators.
In: AM J HUM GENET, Vol. 99, No. 4, 06.10.2016, p. 903-911.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation
AU - Ghoussaini, Maya
AU - French, Juliet D
AU - Michailidou, Kyriaki
AU - Nord, Silje
AU - Beesley, Jonathan
AU - Canisus, Sander
AU - Hillman, Kristine M
AU - Kaufmann, Susanne
AU - Sivakumaran, Haran
AU - Moradi Marjaneh, Mahdi
AU - Lee, Jason S
AU - Dennis, Joe
AU - Bolla, Manjeet K
AU - Wang, Qin
AU - Dicks, Ed
AU - Milne, Roger L
AU - Hopper, John L
AU - Southey, Melissa C
AU - Schmidt, Marjanka K
AU - Broeks, Annegien
AU - Muir, Kenneth
AU - Lophatananon, Artitaya
AU - Fasching, Peter A
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - Sawyer, Elinor J
AU - Tomlinson, Ian
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Bojesen, Stig E
AU - Flyger, Henrik
AU - Benitez, Javier
AU - González-Neira, Anna
AU - Alonso, M Rosario
AU - Pita, Guillermo
AU - Neuhausen, Susan L
AU - Anton-Culver, Hoda
AU - Brenner, Hermann
AU - Arndt, Volker
AU - Meindl, Alfons
AU - Schmutzler, Rita K
AU - Brauch, Hiltrud
AU - Hamann, Ute
AU - Tessier, Daniel C
AU - Vincent, Daniel
AU - Nevanlinna, Heli
AU - Khan, Sofia
AU - Matsuo, Keitaro
AU - Ito, Hidemi
AU - Dörk, Thilo
AU - Bogdanova, Natalia V
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kosma, Veli-Matti
AU - Wu, Anna H
AU - van den Berg, David
AU - Lambrechts, Diether
AU - Floris, Giuseppe
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Radice, Paolo
AU - Barile, Monica
AU - Couch, Fergus J
AU - Hallberg, Emily
AU - Giles, Graham
AU - Haiman, Christopher A
AU - Le Marchand, Loic
AU - Goldberg, Mark S
AU - Teo, Soo-Hwang
AU - Yip, Cheng Har
AU - Borresen-Dale, Anne-Lise
AU - Zheng, Wei
AU - Cai, Qiuyin
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Andrulis, Irene L
AU - Devilee, Peter
AU - Tollenaar, Rob A E M
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Hall, Per
AU - Czene, Kamila
AU - Brand, Judith S
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Hooning, Maartje J
AU - Koppert, Linetta B
AU - Li, Jingmei
AU - Shu, Xiao-Ou
AU - Zheng, Ying
AU - Cox, Angela
AU - Cross, Simon S
AU - Shah, Mitul
AU - Rhenius, Valerie
AU - Choi, Ji-Yeob
AU - Kang, Daehee
AU - Hartman, Mikael
AU - Chia, Kee Seng
AU - Kabisch, Maria
AU - Torres, Diana
AU - Luccarini, Craig
AU - Conroy, Don M
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Sangrajrang, Suleeporn
AU - Brennan, Paul
AU - Olswold, Curtis
AU - Slager, Susan
AU - Shen, Chen-Yang
AU - Hou, Ming-Feng
AU - Swerdlow, Anthony
AU - Schoemaker, Minouk J
AU - Simard, Jacques
AU - Pharoah, Paul D P
AU - Kristensen, Vessela
AU - Chenevix-Trench, Georgia
AU - Easton, Douglas F
AU - Dunning, Alison M
AU - Edwards, Stacey L
AU - kConFab/AOCS Investigators
N1 - Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
AB - Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
KW - Journal Article
U2 - 10.1016/j.ajhg.2016.07.017
DO - 10.1016/j.ajhg.2016.07.017
M3 - SCORING: Journal article
C2 - 27640304
VL - 99
SP - 903
EP - 911
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 4
ER -