Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
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Date
2016-04-01Author
Dunning, AM
Michailidou, K
Kuchenbaecker, KB
Thompson, D
French, JD
Beesley, J
Healey, CS
Kar, S
Pooley, KA
Lopez-Knowles, E
Dicks, E
Barrowdale, D
Sinnott-Armstrong, NA
Sallari, RC
Hillman, KM
Kaufmann, S
Sivakumaran, H
Moradi Marjaneh, M
Lee, JS
Hills, M
Jarosz, M
Drury, S
Canisius, S
Bolla, MK
Dennis, J
Wang, Q
Hopper, JL
Southey, MC
Broeks, A
Schmidt, MK
Lophatananon, A
Muir, K
Beckmann, MW
Fasching, PA
Dos-Santos-Silva, I
Peto, J
Sawyer, EJ
Tomlinson, I
Burwinkel, B
Marme, F
Guénel, P
Truong, T
Bojesen, SE
Flyger, H
González-Neira, A
Perez, JIA
Anton-Culver, H
Eunjung, L
Arndt, V
Brenner, H
Meindl, A
Schmutzler, RK
Brauch, H
Hamann, U
Aittomäki, K
Blomqvist, C
Ito, H
Matsuo, K
Bogdanova, N
Dörk, T
Lindblom, A
Margolin, S
Kosma, V-M
Mannermaa, A
Tseng, C-C
Wu, AH
Lambrechts, D
Wildiers, H
Chang-Claude, J
Rudolph, A
Peterlongo, P
Radice, P
Olson, JE
Giles, GG
Milne, RL
Haiman, CA
Henderson, BE
Goldberg, MS
Teo, SH
Yip, CH
Nord, S
Borresen-Dale, A-L
Kristensen, V
Long, J
Zheng, W
Pylkäs, K
Winqvist, R
Andrulis, IL
Knight, JA
Devilee, P
Seynaeve, C
Figueroa, J
Sherman, ME
Czene, K
Darabi, H
Hollestelle, A
van den Ouweland, AMW
Humphreys, K
Gao, Y-T
Shu, X-O
Cox, A
Cross, SS
Blot, W
Cai, Q
Ghoussaini, M
Perkins, BJ
Shah, M
Choi, J-Y
Kang, D
Lee, SC
Hartman, M
Kabisch, M
Torres, D
Jakubowska, A
Lubinski, J
Brennan, P
Sangrajrang, S
Ambrosone, CB
Toland, AE
Shen, C-Y
Wu, P-E
Orr, N
Swerdlow, A
McGuffog, L
Healey, S
Lee, A
Kapuscinski, M
John, EM
Terry, MB
Daly, MB
Goldgar, DE
Buys, SS
Janavicius, R
Tihomirova, L
Tung, N
Dorfling, CM
van Rensburg, EJ
Neuhausen, SL
Ejlertsen, B
Hansen, TVO
Osorio, A
Benitez, J
Rando, R
Weitzel, JN
Bonanni, B
Peissel, B
Manoukian, S
Papi, L
Ottini, L
Konstantopoulou, I
Apostolou, P
Garber, J
Rashid, MU
Frost, D
EMBRACE,
Izatt, L
Ellis, S
Godwin, AK
Arnold, N
Niederacher, D
Rhiem, K
Bogdanova-Markov, N
Sagne, C
Stoppa-Lyonnet, D
Damiola, F
GEMO Study Collaborators,
Sinilnikova, OM
Mazoyer, S
Isaacs, C
Claes, KBM
De Leeneer, K
de la Hoya, M
Caldes, T
Nevanlinna, H
Khan, S
Mensenkamp, AR
HEBON,
Hooning, MJ
Rookus, MA
Kwong, A
Olah, E
Diez, O
Brunet, J
Pujana, MA
Gronwald, J
Huzarski, T
Barkardottir, RB
Laframboise, R
Soucy, P
Montagna, M
Agata, S
Teixeira, MR
kConFab Investigators,
Park, SK
Lindor, N
Couch, FJ
Tischkowitz, M
Foretova, L
Vijai, J
Offit, K
Singer, CF
Rappaport, C
Phelan, CM
Greene, MH
Mai, PL
Rennert, G
Imyanitov, EN
Hulick, PJ
Phillips, K-A
Piedmonte, M
Mulligan, AM
Glendon, G
Bojesen, A
Thomassen, M
Caligo, MA
Yoon, S-Y
Friedman, E
Laitman, Y
Borg, A
von Wachenfeldt, A
Ehrencrona, H
Rantala, J
Olopade, OI
Ganz, PA
Nussbaum, RL
Gayther, SA
Nathanson, KL
Domchek, SM
Arun, BK
Mitchell, G
Karlan, BY
Lester, J
Maskarinec, G
Woolcott, C
Scott, C
Stone, J
Apicella, C
Tamimi, R
Luben, R
Khaw, K-T
Helland, Å
Haakensen, V
Dowsett, M
Pharoah, PDP
Simard, J
Hall, P
García-Closas, M
Vachon, C
Chenevix-Trench, G
Antoniou, AC
Easton, DF
Edwards, SL
Type
Journal Article
Metadata
Show full item recordAbstract
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Subject
EMBRACE
GEMO Study Collaborators
HEBON
kConFab Investigators
Chromosomes, Human, Pair 6
Humans
Breast Neoplasms
Genetic Predisposition to Disease
Carrier Proteins
Cell Cycle Proteins
Estrogen Receptor alpha
Risk Factors
Gene Expression
Gene Expression Regulation, Neoplastic
Base Sequence
Protein Binding
Phenotype
Polymorphism, Single Nucleotide
Female
Genetic Association Studies
Research team
Complex Trait Genetics
Aetiological Epidemiology
Endocrinology
Language
eng
Date accepted
2016-02-05
License start date
2016-04
Citation
Nature genetics, 2016, 48 (4), pp. 374 - 386
Publisher
NATURE PUBLISHING GROUP