Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
;
Isabel
Dos-Santos-Silva
;
Olivia
Fletcher
;
Nichola
Johnson
;
Manjeet K
Bolla
;
Qin
Wang
;
Joe
Dennis
;
Elinor J
Sawyer
;
Timothy
Cheng
;
Ian
Tomlinson
;
Michael J
Kerin
;
Nicola
Miller
;
Frederik
Marmé
;
Harald M
Surowy
;
Barbara
Burwinkel
;
Pascal
Guénel
;
Thérèse
Truong
;
Florence
Menegaux
;
Claire
Mulot
;
Stig E
Bojesen
;
Børge G
Nordestgaard
;
Sune F
Nielsen
;
Henrik
Flyger
;
Javier
Benitez
;
M Pilar
Zamora
;
Jose Ignacio
Arias Perez
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Primitiva
Menéndez
;
Anna
González-Neira
;
Guillermo
Pita
;
M Rosario
Alonso
;
Nuria
Alvarez
;
Daniel
Herrero
;
Hoda
Anton-Culver
;
Hermann
Brenner
;
Aida Karina
Dieffenbach
;
Volker
Arndt
;
Christa
Stegmaier
;
Alfons
Meindl
;
Peter
Lichtner
;
Rita K
Schmutzler
;
Bertram
Müller-Myhsok
;
Hiltrud
Brauch
;
Thomas
Brüning
;
Yon-Dschun
Ko
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GENICA Network
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Daniel C
Tessier
;
Daniel
Vincent
;
Francois
Bacot
;
Heli
Nevanlinna
;
Kristiina
Aittomäki
;
Carl
Blomqvist
;
Sofia
Khan
;
Keitaro
Matsuo
;
Hidemi
Ito
;
Hiroji
Iwata
;
Akiyo
Horio
;
Natalia V
Bogdanova
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Natalia N
Antonenkova
;
Thilo
Dörk
;
Annika
Lindblom
;
Sara
Margolin
;
Arto
Mannermaa
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Vesa
Kataja
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Veli-Matti
Kosma
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Jaana M
Hartikainen
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kConFab Investigators
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Australian Ovarian Cancer Study Group
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Anna H
Wu
;
Chiu-Chen
Tseng
;
David
Van Den Berg
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Daniel O
Stram
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Patrick
Neven
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Els
Wauters
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Hans
Wildiers
;
Diether
Lambrechts
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Jenny
Chang-Claude
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Anja
Rudolph
;
Petra
Seibold
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Dieter
Flesch-Janys
;
Paolo
Radice
;
Paolo
Peterlongo
;
Siranoush
Manoukian
;
Bernardo
Bonanni
;
Fergus J
Couch
;
Xianshu
Wang
;
Celine
Vachon
;
Kristen
Purrington
;
Graham G
Giles
;
Roger L
Milne
;
Catriona
Mclean
;
Christopher A
Haiman
;
Brian E
Henderson
;
Fredrick
Schumacher
;
Loic
Le Marchand
;
Jacques
Simard
;
Mark S
Goldberg
;
France
Labrèche
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Martine
Dumont
;
Soo Hwang
Teo
;
Cheng Har
Yip
;
Norhashimah
Hassan
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Eranga Nishanthie
Vithana
;
Vessela
Kristensen
;
Wei
Zheng
;
Sandra
Deming-Halverson
;
Martha J
Shrubsole
;
Jirong
Long
;
Robert
Winqvist
;
Katri
Pylkäs
;
Arja
Jukkola-Vuorinen
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Saila
Kauppila
;
Irene L
Andrulis
;
Julia A
Knight
;
Gord
Glendon
;
Sandrine
Tchatchou
;
Peter
Devilee
;
Robert AEM
Tollenaar
;
Caroline
Seynaeve
;
Christi J
Van Asperen
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Montserrat
García-Closas
;
Jonine
Figueroa
;
Jolanta
Lissowska
;
Louise
Brinton
;
Kamila
Czene
;
Hatef
Darabi
;
Mikael
Eriksson
;
Judith S
Brand
;
Maartje J
Hooning
;
Antoinette
Hollestelle
;
Ans MW
Van Den Ouweland
;
Agnes
Jager
;
Jingmei
Li
;
Jianjun
Liu
;
Keith
Humphreys
;
Xiao-Ou
Shu
;
Wei
Lu
;
Yu-Tang
Gao
;
Hui
Cai
;
Simon S
Cross
;
Malcolm WR
Reed
;
William
Blot
;
Lisa B
Signorello
;
Qiuyin
Cai
;
Paul DP
Pharoah
;
Barbara
Perkins
;
Mitul
Shah
;
Fiona M
Blows
;
Daehee
Kang
;
Keun-Young
Yoo
;
Dong-Young
Noh
;
Mikael
Hartman
;
Hui
Miao
;
Kee Seng
Chia
;
Thomas Choudary
Putti
;
Ute
Hamann
;
Craig
Luccarini
;
Caroline
Baynes
;
Shahana
Ahmed
;
Mel
Maranian
;
Catherine S
Healey
;
Anna
Jakubowska
;
Jan
Lubinski
;
Katarzyna
Jaworska-Bieniek
;
Katarzyna
Durda
;
Suleeporn
Sangrajrang
;
Valerie
Gaborieau
;
Paul
Brennan
;
James
Mckay
;
Susan
Slager
;
Amanda E
Toland
;
Drakoulis
Yannoukakos
;
Chen-Yang
Shen
;
Chia-Ni
Hsiung
;
Pei-Ei
Wu
;
Shian-Ling
Ding
;
Alan
Ashworth
;
Michael
Jones
;
Nick
Orr
;
Anthony J
Swerdlow
;
Helen
Tsimiklis
;
Enes
Makalic
;
Daniel F
Schmidt
;
Quang M
Bui
;
Stephen J
Chanock
;
David J
Hunter
;
Rebecca
Hein
;
Norbert
Dahmen
;
Lars
Beckmann
;
Kirsimari
Aaltonen
;
Taru A
Muranen
;
Tuomas
Heikkinen
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Astrid
Irwanto
;
Nazneen
Rahman
;
Clare A
Turnbull
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Breast and Ovarian Cancer Susceptibility (BOCS) Study
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Quinten
Waisfisz
;
Hanne EJ
Meijers-Heijboer
;
Muriel A
Adank
;
Rob B
Van Der Luijt
;
Per
Hall
;
Georgia
Chenevix-Trench
;
Alison
Dunning
;
Douglas F
Easton
;
Angela
Cox
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(2014)
Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Human molecular genetics, 24 (1).
pp. 285-298.
ISSN 0964-6906
DOI: 10.1093/hmg/ddu431
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.