Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
Antoniou
Antonis C
AC
Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK. antonis@srl.cam.ac.uk
Sinilnikova
Olga M
OM
McGuffog
Lesley
L
Healey
Sue
S
Nevanlinna
Heli
H
Heikkinen
Tuomas
T
Simard
Jacques
J
Spurdle
Amanda B
AB
Beesley
Jonathan
J
Chen
Xiaoqing
X
Neuhausen
Susan L
SL
Ding
Yuan C
YC
Couch
Fergus J
FJ
Wang
Xianshu
X
Fredericksen
Zachary
Z
Peterlongo
Paolo
P
Peissel
Bernard
B
Bonanni
Bernardo
B
Viel
Alessandra
A
Bernard
Loris
L
Radice
Paolo
P
Szabo
Csilla I
CI
Foretova
Lenka
L
Zikan
Michal
M
Claes
Kathleen
K
Greene
Mark H
MH
Mai
Phuong L
PL
Rennert
Gad
G
Lejbkowicz
Flavio
F
Andrulis
Irene L
IL
Ozcelik
Hilmi
H
Glendon
Gord
G
Gerdes
Anne-Marie
AM
Thomassen
Mads
M
Sunde
Lone
L
Caligo
Maria A
MA
Laitman
Yael
Y
Kontorovich
Tair
T
Cohen
Shimrit
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Kaufman
Bella
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E
Baruch
Ruth Gershoni
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Friedman
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Ehrencrona
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Per
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Nathanson
Katherine L
KL
Osorio
Ana
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Ignacio
I
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Adriana
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Benítez
Javier
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Hamann
Ute
U
Hogervorst
Frans B L
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Matti A
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CM
Waisfisz
Quinten
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van Roozendaal
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Margaret
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Debra
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Oliver
Clare
C
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Radka
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DG
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Fiona
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Rosalind
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Diana
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Shirley
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David
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Alexander
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Esther M
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Buys
Saundra S
SS
Daly
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MB
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John L
JL
Terry
Mary Beth
MB
Yassin
Yosuf
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Christian
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Gschwantler-Kaulich
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Barkardottir
Rosa Bjork
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Kirchhoff
Tomas
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Kristi
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Kenneth
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John F
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Imyanitov
Evgeny N
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Anna
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Schmutzler
Rita K
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Versmold
Beatrix
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Engel
Christoph
C
Meindl
Alfons
A
Ditsch
Nina
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Arnold
Norbert
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Niederacher
Dieter
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Deissler
Helmut
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Fiebig
Britta
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Christian
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Ines
I
Gadzicki
Dorothea
D
Caldes
Trinidad
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de la Hoya
Miguel
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Pooley
Karen A
KA
Easton
Douglas F
DF
Chenevix-Trench
Georgia
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D019313:BRCA1 Protein; D024682:BRCA2 Protein; C489183:LSP1 protein, human; D008840:Microfilament Proteins