Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.
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Isabel
dos Santos Silva
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Olivia
Fletcher
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Nichola
Johnson
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Elinor
Sawyer
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Ian
Tomlinson
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Michael
Kerin
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Barbara
Burwinkel
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Federik
Marme
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Andreas
Schneeweiss
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Christof
Sohn
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Stig
Bojesen
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Henrik
Flyger
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Børge G
Nordestgaard
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Javier
Benítez
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Roger L
Milne
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Jose
Ignacio Arias
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M Pilar
Zamora
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Hermann
Brenner
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Heiko
Müller
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Volker
Arndt
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Nazneen
Rahman
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Clare
Turnbull
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Sheila
Seal
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Anthony
Renwick
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Hiltrud
Brauch
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Christina
Justenhoven
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Thomas
Brüning
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GENICA Network
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Jenny
Chang-Claude
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Rebecca
Hein
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Shan
Wang-Gohrke
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Thilo
Dörk
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Peter
Schürmann
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Michael
Bremer
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Peter
Hillemanns
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Heli
Nevanlinna
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Tuomas
Heikkinen
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Kristiina
Aittomäki
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Carl
Blomqvist
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Natalia
Bogdanova
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Natalia
Antonenkova
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Yuri I
Rogov
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Johann Hinrich
Karstens
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Marina
Bermisheva
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Darya
Prokofieva
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Shamil Hanafievich
Gantcev
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Elza
Khusnutdinova
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Annika
Lindblom
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Sara
Margolin
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Georgia
Chenevix-Trench
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Jonathan
Beesley
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Xiaoqing
Chen
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kConFab AOCS Management Group
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Arto
Mannermaa
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Veli-Matti
Kosma
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Ylermi
Soini
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Vesa
Kataja
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Diether
Lambrechts
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Betül T
Yesilyurt
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Marie-Rose
Chrisiaens
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Stephanie
Peeters
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Paolo
Radice
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Paolo
Peterlongo
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Siranoush
Manoukian
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Monica
Barile
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Fergus
Couch
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Adam M
Lee
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Robert
Diasio
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Xianshu
Wang
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Graham G
Giles
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Gianluca
Severi
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Laura
Baglietto
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Catriona
Maclean
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Ken
Offit
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Mark
Robson
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Vijai
Joseph
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Mia
Gaudet
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Esther M
John
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Robert
Winqvist
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Katri
Pylkäs
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Arja
Jukkola-Vuorinen
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Mervi
Grip
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Irene
Andrulis
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Julia A
Knight
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Anna Marie
Mulligan
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Frances P
O'Malley
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Louise A
Brinton
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Mark E
Sherman
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Jolanta
Lissowska
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Stephen J
Chanock
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Maartje
Hooning
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John WM
Martens
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Ans MW
van den Ouweland
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J Margriet
Collée
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Per
Hall
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Kamila
Czene
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Angela
Cox
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Ian W
Brock
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Malcolm WR
Reed
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Simon S
Cross
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Paul
Pharoah
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Alison M
Dunning
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Daehee
Kang
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Keun-Young
Yoo
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Dong-Young
Noh
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Sei-Hyun
Ahn
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Anna
Jakubowska
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Jan
Lubinski
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Katarzyna
Jaworska
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Katarzyna
Durda
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Suleeporn
Sangrajrang
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Valerie
Gaborieau
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Paul
Brennan
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James
McKay
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Chen-Yang
Shen
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Shian-ling
Ding
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Huan-Ming
Hsu
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Jyh-Cherng
Yu
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Hoda
Anton-Culver
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Argyrios
Ziogas
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Alan
Ashworth
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Anthony
Swerdlow
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Michael
Jones
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Nick
Orr
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Amy
Trentham-Dietz
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Kathleen
Egan
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Polly
Newcomb
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Linda
Titus-Ernstoff
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Doug
Easton
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Amanda B
Spurdle
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(2011)
Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.
Human molecular genetics, 20 (23).
pp. 4693-4706.
ISSN 0964-6906
DOI: 10.1093/hmg/ddr368
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.