title: Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.
abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.
authors: Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands. a.broeks@nki.nl
authors: Annegien
authors: A
authors: Broeks
authors: Marjanka K
authors: MK
authors: Schmidt
authors: Mark E
authors: ME
authors: Sherman
authors: Fergus J
authors: FJ
authors: Couch
authors: John L
authors: JL
authors: Hopper
authors: Gillian S
authors: GS
authors: Dite
authors: Carmel
authors: C
authors: Apicella
authors: Letitia D
authors: LD
authors: Smith
authors: Fleur
authors: F
authors: Hammet
authors: Melissa C
authors: MC
authors: Southey
authors: Laura J
authors: LJ
authors: Van 't Veer
authors: Renate
authors: R
authors: de Groot
authors: Vincent T H B M
authors: VT
authors: Smit
authors: Peter A
authors: PA
authors: Fasching
authors: Matthias W
authors: MW
authors: Beckmann
authors: Sebastian
authors: S
authors: Jud
authors: Arif B
authors: AB
authors: Ekici
authors: Arndt
authors: A
authors: Hartmann
authors: Alexander
authors: A
authors: Hein
authors: Ruediger
authors: R
authors: Schulz-Wendtland
authors: Barbara
authors: B
authors: Burwinkel
authors: Frederik
authors: F
authors: Marme
authors: Andreas
authors: A
authors: Schneeweiss
authors: Hans-Peter
authors: HP
authors: Sinn
authors: Christof
authors: C
authors: Sohn
authors: Sandrine
authors: S
authors: Tchatchou
authors: Stig E
authors: SE
authors: Bojesen
authors: Børge G
authors: BG
authors: Nordestgaard
authors: Henrik
authors: H
authors: Flyger
authors: David D
authors: DD
authors: Ørsted
authors: Diljit
authors: D
authors: Kaur-Knudsen
authors: Roger L
authors: RL
authors: Milne
authors: Jose I Arias
authors: JI
authors: Pérez
authors: Pilar
authors: P
authors: Zamora
authors: Primitiva Menéndez
authors: PM
authors: Rodríguez
authors: Javier
authors: J
authors: Benítez
authors: Hiltrud
authors: H
authors: Brauch
authors: Christina
authors: C
authors: Justenhoven
authors: Yon-Dschun
authors: YD
authors: Ko
authors: Ute
authors: U
authors: Hamann
authors: Hans-Peter
authors: HP
authors: Fischer
authors: Thomas
authors: T
authors: Brüning
authors: Beate
authors: B
authors: Pesch
authors: Jenny
authors: J
authors: Chang-Claude
authors: Shan
authors: S
authors: Wang-Gohrke
authors: Michael
authors: M
authors: Bremer
authors: Johann H
authors: JH
authors: Karstens
authors: Peter
authors: P
authors: Hillemanns
authors: Thilo
authors: T
authors: Dörk
authors: Heli A
authors: HA
authors: Nevanlinna
authors: Tuomas
authors: T
authors: Heikkinen
authors: Päivi
authors: P
authors: Heikkilä
authors: Carl
authors: C
authors: Blomqvist
authors: Kristiina
authors: K
authors: Aittomäki
authors: Kirsimari
authors: K
authors: Aaltonen
authors: Annika
authors: A
authors: Lindblom
authors: Sara
authors: S
authors: Margolin
authors: Arto
authors: A
authors: Mannermaa
authors: Veli-Matti
authors: VM
authors: Kosma
authors: Jaana M
authors: JM
authors: Kauppinen
authors: Vesa
authors: V
authors: Kataja
authors: Päivi
authors: P
authors: Auvinen
authors: Matti
authors: M
authors: Eskelinen
authors: Ylermi
authors: Y
authors: Soini
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Amanda B
authors: AB
authors: Spurdle
authors: Jonathan
authors: J
authors: Beesley
authors: Xiaoqing
authors: X
authors: Chen
authors: Helene
authors: H
authors: Holland
authors: Diether
authors: D
authors: Lambrechts
authors: Bart
authors: B
authors: Claes
authors: Thijs
authors: T
authors: Vandorpe
authors: Patrick
authors: P
authors: Neven
authors: Hans
authors: H
authors: Wildiers
authors: Dieter
authors: D
authors: Flesch-Janys
authors: Rebecca
authors: R
authors: Hein
authors: Thomas
authors: T
authors: Löning
authors: Matthew
authors: M
authors: Kosel
authors: Zachary S
authors: ZS
authors: Fredericksen
authors: Xianshu
authors: X
authors: Wang
authors: Graham G
authors: GG
authors: Giles
authors: Laura
authors: L
authors: Baglietto
authors: Gianluca
authors: G
authors: Severi
authors: Catriona
authors: C
authors: McLean
authors: Christopher A
authors: CA
authors: Haiman
authors: Brian E
authors: BE
authors: Henderson
authors: Loic
authors: L
authors: Le Marchand
authors: Laurence N
authors: LN
authors: Kolonel
authors: Grethe Grenaker
authors: GG
authors: Alnæs
authors: Vessela
authors: V
authors: Kristensen
authors: Anne-Lise
authors: AL
authors: Børresen-Dale
authors: David J
authors: DJ
authors: Hunter
authors: Susan E
authors: SE
authors: Hankinson
authors: Irene L
authors: IL
authors: Andrulis
authors: Anna Marie
authors: AM
authors: Mulligan
authors: Frances P
authors: FP
authors: O'Malley
authors: Peter
authors: P
authors: Devilee
authors: Petra E A
authors: PE
authors: Huijts
authors: Rob A E M
authors: RA
authors: Tollenaar
authors: Christi J
authors: CJ
authors: Van Asperen
authors: Caroline S
authors: CS
authors: Seynaeve
authors: Stephen J
authors: SJ
authors: Chanock
authors: Jolanta
authors: J
authors: Lissowska
authors: Louise
authors: L
authors: Brinton
authors: Beata
authors: B
authors: Peplonska
authors: Jonine
authors: J
authors: Figueroa
authors: Xiaohong R
authors: XR
authors: Yang
authors: Maartje J
authors: MJ
authors: Hooning
authors: Antoinette
authors: A
authors: Hollestelle
authors: Rogier A
authors: RA
authors: Oldenburg
authors: Agnes
authors: A
authors: Jager
authors: Mieke
authors: M
authors: Kriege
authors: Bahar
authors: B
authors: Ozturk
authors: Geert J L H
authors: GJ
authors: van Leenders
authors: Per
authors: P
authors: Hall
authors: Kamila
authors: K
authors: Czene
authors: Keith
authors: K
authors: Humphreys
authors: Jianjun
authors: J
authors: Liu
authors: Angela
authors: A
authors: Cox
authors: Daniel
authors: D
authors: Connley
authors: Helen E
authors: HE
authors: Cramp
authors: Simon S
authors: SS
authors: Cross
authors: Sabapathy P
authors: SP
authors: Balasubramanian
authors: Malcolm W R
authors: MW
authors: Reed
authors: Alison M
authors: AM
authors: Dunning
authors: Douglas F
authors: DF
authors: Easton
authors: Manjeet K
authors: MK
authors: Humphreys
authors: Carlos
authors: C
authors: Caldas
authors: Fiona
authors: F
authors: Blows
authors: Kristy
authors: K
authors: Driver
authors: Elena
authors: E
authors: Provenzano
authors: Jan
authors: J
authors: Lubinski
authors: Anna
authors: A
authors: Jakubowska
authors: Tomasz
authors: T
authors: Huzarski
authors: Tomasz
authors: T
authors: Byrski
authors: Cezary
authors: C
authors: Cybulski
authors: Bohdan
authors: B
authors: Gorski
authors: Jacek
authors: J
authors: Gronwald
authors: Paul
authors: P
authors: Brennan
authors: Suleeporn
authors: S
authors: Sangrajrang
authors: Valerie
authors: V
authors: Gaborieau
authors: Chen-Yang
authors: CY
authors: Shen
authors: Chia-Ni
authors: CN
authors: Hsiung
authors: Jyh-Cherng
authors: JC
authors: Yu
authors: Shou-Tung
authors: ST
authors: Chen
authors: Giu-Cheng
authors: GC
authors: Hsu
authors: Ming-Feng
authors: MF
authors: Hou
authors: Chiun-Sheng
authors: CS
authors: Huang
authors: Hoda
authors: H
authors: Anton-Culver
authors: Argyrios
authors: A
authors: Ziogas
authors: Paul D P
authors: PD
authors: Pharoah
authors: Montserrat
authors: M
authors: Garcia-Closas
references: Breast Cancer Res Treat. 2005 Mar;90(2):127-37
references: 15803359
references: J Natl Cancer Inst. 2004 Mar 17;96(6):434-42
references: 15026468
references: Breast Cancer Res. 2007;9(5):R65
references: 17910759
references: PLoS Med. 2010 May 25;7(5):e1000279
references: 20520800
references: Br J Cancer. 1992 Aug;66(2):273-80
references: 1380281
references: Nature. 2007 Jun 28;447(7148):1087-93
references: 17529967
references: N Engl J Med. 2008 Jun 26;358(26):2796-803
references: 18579814
references: Cancer Res. 2009 Nov 1;69(21):8302-9
references: 19843853
references: Nat Genet. 2009 Mar;41(3):324-8
references: 19219042
references: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references: 11553815
references: Mod Pathol. 2008 May;21 Suppl 2:S8-S15
references: 18437174
references: Breast Cancer Res Treat. 2009 May;115(1):185-92
references: 18523885
references: JAMA. 2010 Jul 28;304(4):426-34
references: 20664043
references: Am J Hum Genet. 2008 Apr;82(4):937-48
references: 18355772
references: J Natl Cancer Inst. 2009 Jul 15;101(14):1012-8
references: 19567422
references: Breast Cancer Res Treat. 2010 Jan;119(1):119-26
references: 19669409
references: Clin Cancer Res. 2008 Dec 15;14(24):8000-9
references: 19088016
references: Nat Genet. 2010 Oct;42(10):885-92
references: 20852631
references: Nature. 2000 Aug 17;406(6797):747-52
references: 10963602
references: Breast Cancer Res Treat. 2010 Feb;119(3):685-99
references: 20012355
references: Breast Cancer Res. 2006;8(4):R43
references: 16859501
references: BMC Genomics. 2006 Sep 11;7:231
references: 16965636
references: Cancer Res. 2007 Nov 1;67(21):10608-17
references: 17968031
references: Hum Mol Genet. 2009 Nov 15;18(22):4442-56
references: 19656774
references: Nat Genet. 2008 Jun;40(6):703-6
references: 18438407
references: PLoS Genet. 2008 Apr 25;4(4):e1000054
references: 18437204
references: Clin Cancer Res. 2004 Aug 15;10(16):5367-74
references: 15328174
references: Nat Genet. 2007 Mar;39(3):352-8
references: 17293864
references: Cancer Epidemiol Biomarkers Prev. 2004 Oct;13(10):1558-68
references: 15466970
references: Eur J Cancer. 2009 Sep;45 Suppl 1:27-40
references: 19775602
references: Nat Genet. 2007 Jul;39(7):870-4
references: 17529973
references: J Natl Cancer Inst. 2008 Feb 6;100(3):218-21
references: 18230800
references: J Clin Oncol. 2002 May 1;20(9):2310-8
references: 11981002
references: Nat Genet. 2009 May;41(5):585-90
references: 19330027
references: Nat Genet. 2007 Jul;39(7):865-9
references: 17529974
references: Cancer Res. 2010 Dec 1;70(23):9742-54
references: 21118973
references: Breast Cancer Res. 2007;9(6):113
references: 18036273
references: J Natl Cancer Inst. 2011 Feb 2;103(3):250-63
references: 21191117
references: Cancer Epidemiol Biomarkers Prev. 2004 Jul;13(7):1128-35
references: 15247123