Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk.
Germ line mutations in several genes (BRCA1, BRCA2, and CHEK2) whose products are involved in the DNA damage-signaling pathway have been implicated in prostate cancer risk. To identify additional genes in this pathway that might confer susceptibility to this cancer, we analyzed a recently identified DNA damage-response gene, p53AIP1 (a gene encoding for p53-regulated apoptosis-inducing protein 1), for genetic variants in prostate cancer. Five novel germ line variants were identified. The two truncating variants (Ser(32)Stop and Arg(21)insG) were found in 3% (4 of 132) of unselected prostate tumor samples. Genotyping of the two variants in an additional 393 men with sporadic prostate cancer showed a frequency of 3.1% (12 of 393) in contrast to 0.6% (2 of 327) in 327 unaffected men (Fisher's exact test, P = 0.018), with an odds ratio (OR) of 5.1 [95% confidence interval (95% CI), 1.1-23.0]. In addition, two of six tumors carrying the truncating variants were associated with loss of heterozygosity of the wild-type alleles, suggesting that p53AIP1 may act as a tumor suppressor. We also showed that the truncated p53AIP1 was unable to induce apoptosis and suppress cell growth in HeLa and COS-7 cells. These results suggest that loss-of-function variants in p53AIP1 associated with the risk of sporadic prostate cancer and further support the concept that the genetic defects in the DNA damage-response genes play an important role in the development of prostate cancer.
Wang
Xianshu
X
Department of Laboratory Medicine, Mayo Clinic/Mayo Clinical Medical College, Rochester, Minnesota 55905, USA.
Wang
Fengwei
F
Taniguchi
Ken
K
Seelan
Ratnam S
RS
Wang
Liang
L
Zarfas
Katherine E
KE
McDonnell
Shannon K
SK
Qian
Chiping
C
Pan
Kaifeng
K
Lu
Youyong
Y
Shridhar
Viji
V
Couch
Fergus J
FJ
Tindall
Donald J
DJ
Beebe-Dimmer
Jennifer L
JL
Cooney
Kathleen A
KA
Isaacs
William B
WB
Jacobsen
Steven J
SJ
Schaid
Daniel J
DJ
Thibodeau
Stephen N
SN
Liu
Wanguo
W
D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D004249:DNA Damage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics; D012306:Risk
D051017:Apoptosis Regulatory Proteins; C414742:P53AIP1 protein, human