Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.
Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).
Frank
Bernd
B
Helmholtz-University Group Molecular Epidemiology, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Wiestler
Miriam
M
Kropp
Silke
S
Hemminki
Kari
K
Spurdle
Amanda B
AB
Sutter
Christian
C
Wappenschmidt
Barbara
B
Chen
Xiaoqing
X
Beesley
Jonathan
J
Hopper
John L
JL
Meindl
Alfons
A
Kiechle
Marion
M
Slanger
Tracy
T
Bugert
Peter
P
Schmutzler
Rita K
RK
Bartram
Claus R
CR
Flesch-Janys
Dieter
D
Mutschelknauss
Elke
E
Ashton
Katie
K
Salazar
Ramona
R
Webb
Emily
E
Hamann
Ute
U
Brauch
Hiltrud
H
Justenhoven
Christina
C
Ko
Yon-Dschun
YD
Brüning
Thomas
T
Silva
Isabel dos Santos
Idos S
Johnson
Nichola
N
Pharoah
Paul P D
PP
Dunning
Alison M
AM
Pooley
Karen A
KA
Chang-Claude
Jenny
J
Easton
Douglas F
DF
Peto
Julian
J
Houlston
Richard
R
Chenevix-Trench
Georgia
G
Fletcher
Olivia
O
Burwinkel
Barbara
B
D054758:A Kinase Anchor Proteins / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007532:Isoleucine; D015810:Linkage Disequilibrium; D008715:Methionine; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D044465:White People / Q000235:genetics
D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D003598:Cytoskeletal Proteins; D007532:Isoleucine; D008715:Methionine