RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.
RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.
Antoniou
Antonis C
AC
Cancer Research UK, Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, CB1 8RN, UK. antonis@srl.cam.ac.uk
Sinilnikova
Olga M
OM
Simard
Jacques
J
Léoné
Mélanie
M
Dumont
Martine
M
Neuhausen
Susan L
SL
Struewing
Jeffery P
JP
Stoppa-Lyonnet
Dominique
D
Barjhoux
Laure
L
Hughes
David J
DJ
Coupier
Isabelle
I
Belotti
Muriel
M
Lasset
Christine
C
Bonadona
Valérie
V
Bignon
Yves-Jean
YJ
Rebbeck
Timothy R
TR
Wagner
Theresa
T
Lynch
Henry T
HT
Domchek
Susan M
SM
Nathanson
Katherine L
KL
Garber
Judy E
JE
Weitzel
Jeffrey
J
Narod
Steven A
SA
Tomlinson
Gail
G
Olopade
Olufunmilayo I
OI
Godwin
Andrew
A
Isaacs
Claudine
C
Jakubowska
Anna
A
Lubinski
Jan
J
Gronwald
Jacek
J
Górski
Bohdan
B
Byrski
Tomasz
T
Huzarski
Tomasz
T
Peock
Susan
S
Cook
Margaret
M
Baynes
Caroline
C
Murray
Alexandra
A
Rogers
Mark
M
Daly
Peter A
PA
Dorkins
Huw
H
Schmutzler
Rita K
RK
Versmold
Beatrix
B
Engel
Christoph
C
Meindl
Alfons
A
Arnold
Norbert
N
Niederacher
Dieter
D
Deissler
Helmut
H
Spurdle
Amanda B
AB
Chen
Xiaoqing
X
Waddell
Nicola
N
Cloonan
Nicole
N
Kirchhoff
Tomas
T
Offit
Kenneth
K
Friedman
Eitan
E
Kaufmann
Bella
B
Laitman
Yael
Y
Galore
Gilli
G
Rennert
Gad
G
Lejbkowicz
Flavio
F
Raskin
Leon
L
Andrulis
Irene L
IL
Ilyushik
Eduard
E
Ozcelik
Hilmi
H
Devilee
Peter
P
Vreeswijk
Maaike P G
MP
Greene
Mark H
MH
Prindiville
Sheila A
SA
Osorio
Ana
A
Benitez
Javier
J
Zikan
Michal
M
Szabo
Csilla I
CI
Kilpivaara
Outi
O
Nevanlinna
Heli
H
Hamann
Ute
U
Durocher
Francine
F
Arason
Adalgeir
A
Couch
Fergus J
FJ
Easton
Douglas F
DF
Chenevix-Trench
Georgia
G
D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000517:prevention & control; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics; D005190:Family; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D017931:DNA Primers; C495153:RAD51 protein, human; D051135:Rad51 Recombinase