title: 19p13.1 is a triple-negative-specific breast cancer susceptibility locus.
abstract: The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
authors.affiliation: Departments of Health Sciences Research and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Stevens
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fredericksen
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Alina
authors.initials: A
authors.lastname: Vrieling
authors.forename: Dieter
authors.initials: D
authors.lastname: Flesch-Janys
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.forename: Shan
authors.initials: S
authors.lastname: Wang-Gohrke
authors.forename: Stefan
authors.initials: S
authors.lastname: Nickels
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Joellen
authors.initials: J
authors.lastname: Weaver
authors.forename: Harsh B
authors.initials: HB
authors.lastname: Pathak
authors.forename: Priyanka
authors.initials: P
authors.lastname: Sharma
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Heiko
authors.initials: H
authors.lastname: Müller
authors.forename: Volker
authors.initials: V
authors.lastname: Arndt
authors.forename: Christa
authors.initials: C
authors.lastname: Stegmaier
authors.forename: Penelope
authors.initials: P
authors.lastname: Miron
authors.forename: Drakoulis
authors.initials: D
authors.lastname: Yannoukakos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stavropoulou
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Gogas
authors.forename: Ruth
authors.initials: R
authors.lastname: Swann
authors.forename: Miriam
authors.initials: M
authors.lastname: Dwek
authors.forename: Annie
authors.initials: A
authors.lastname: Perkins
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Zamora
authors.forename: José Ignacio Arias
authors.initials: JI
authors.lastname: Pérez
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.forename: Sune F
authors.initials: SF
authors.lastname: Nielsen
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Henrik
authors.initials: H
authors.lastname: Flyger
authors.forename: Pascal
authors.initials: P
authors.lastname: Guénel
authors.forename: Thérèse
authors.initials: T
authors.lastname: Truong
authors.forename: Florence
authors.initials: F
authors.lastname: Menegaux
authors.forename: Emilie
authors.initials: E
authors.lastname: Cordina-Duverger
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Frederick
authors.initials: F
authors.lastname: Marmé
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Elinor
authors.initials: E
authors.lastname: Sawyer
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kerin
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Isabel
authors.initials: I
authors.lastname: Dos Santos Silva
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Artitaya
authors.initials: A
authors.lastname: Lophatananon
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muir
authors.forename: Puttisak
authors.initials: P
authors.lastname: Puttawibul
authors.forename: Surapon
authors.initials: S
authors.lastname: Wiangnon
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Linde M
authors.initials: LM
authors.lastname: Braaf
authors.forename: Efraim H
authors.initials: EH
authors.lastname: Rosenberg
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Swerdlow
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Nicholas
authors.initials: N
authors.lastname: Orr
authors.forename: Minouk J
authors.initials: MJ
authors.lastname: Schoemaker
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Christina Clarke
authors.initials: CC
authors.lastname: Dur
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Thomas
authors.initials: T
authors.lastname: Dünnebier
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Ulmer
authors.forename: Paul P
authors.initials: PP
authors.lastname: Pharoah
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Humphreys
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Malcom W
authors.initials: MW
authors.lastname: Reed
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Foluso
authors.initials: F
authors.lastname: Ademuyiwa
authors.forename: Helena
authors.initials: H
authors.lastname: Hwang
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Hooning
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.forename: Gord
authors.initials: G
authors.lastname: Glendon
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Arja
authors.initials: A
authors.lastname: Jukkola-Vuorinen
authors.forename: Mervi
authors.initials: M
authors.lastname: Grip
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Grethe Grenaker
authors.initials: GG
authors.lastname: Alnæs
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Kosel
authors.forename: V S
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Susan
authors.initials: S
authors.lastname: Slager
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Monica
authors.initials: M
authors.lastname: Barile
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dieudonne
authors.forename: Marie-Rose
authors.initials: MR
authors.lastname: Christiaens
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis; D012306:Risk
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human