The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.
BACKGROUND
The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.


METHODS
To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.


RESULTS
No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.


CONCLUSIONS
There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.
Sinilnikova
O M
OM
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon, Centre Léon Bérard, Lyon 69373, France. sinilnik@lyon.fnclcc.fr
Antoniou
A C
AC
Simard
J
J
Healey
S
S
Léoné
M
M
Sinnett
D
D
Spurdle
A B
AB
Beesley
J
J
Chen
X
X
Greene
M H
MH
Loud
J T
JT
Lejbkowicz
F
F
Rennert
G
G
Dishon
S
S
Andrulis
I L
IL
Domchek
S M
SM
Nathanson
K L
KL
Manoukian
S
S
Radice
P
P
Konstantopoulou
I
I
Blanco
I
I
Laborde
A L
AL
Durán
M
M
Osorio
A
A
Benitez
J
J
Hamann
U
U
Hogervorst
F B L
FB
van Os
T A M
TA
Gille
H J P
HJ
Peock
S
S
Cook
M
M
Luccarini
C
C
Evans
D G
DG
Lalloo
F
F
Eeles
R
R
Pichert
G
G
Davidson
R
R
Cole
T
T
Cook
J
J
Paterson
J
J
Brewer
C
C
Hughes
D J
DJ
Coupier
I
I
Giraud
S
S
Coulet
F
F
Colas
C
C
Soubrier
F
F
Rouleau
E
E
Bièche
I
I
Lidereau
R
R
Demange
L
L
Nogues
C
C
Lynch
H T
HT
Schmutzler
R K
RK
Versmold
B
B
Engel
C
C
Meindl
A
A
Arnold
N
N
Sutter
C
C
Deissler
H
H
Schaefer
D
D
Froster
U G
UG
Aittomäki
K
K
Nevanlinna
H
H
McGuffog
L
L
Easton
D F
DF
Chenevix-Trench
G
G
Stoppa-Lyonnet
D
D
D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012307:Risk Factors
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
Nat Genet. 2003 Mar;33(3):357-65
12567188
Breast Cancer Res Treat. 2007 Aug;104(2):153-7
17080308
J Med Genet. 2003 Apr;40(4):e34
12676907
Clin Cancer Res. 2005 Jul 15;11(14):5175-80
16033833
Nat Cell Biol. 2008 Sep;10(9):1098-105
19160491
Eur J Hum Genet. 2007 Jan;15(1):110-4
17003841
Cancer Res. 2001 May 15;61(10):4092-7
11358831
Breast Cancer Res. 2007;9(2):104
17466083
Breast Cancer Res Treat. 2008 Oct;111(3):497-504
18026875
Hum Mutat. 2006 Mar;27(3):242-8
16419081
Nat Rev Cancer. 2006 Dec;6(12):909-23
17128209
J Med Genet. 2006 Jun;43(6):531-3
16258005
Cell. 2004 Nov 24;119(5):591-602
15550242
Cancer Res. 2007 Oct 1;67(19):9584-90
17909070
BMC Cancer. 2006 Mar 24;6:80
16563154
Cancer Res. 2009 Jan 15;69(2):663-71
19147582
Clin Cancer Res. 2005 Jul 15;11(14):5098-103
16033823
Oncogene. 2006 Sep 25;25(43):5885-97
16998503
Am J Hum Genet. 2007 Dec;81(6):1186-200
17999359
Br J Cancer. 2008 Sep 16;99(6):974-7
18781154
Am J Hum Genet. 2008 Apr;82(4):937-48
18355772
Nucleic Acids Res. 2006 Mar 06;34(5):1416-26
16522651