TY - JOUR
T1 - Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk
AU - Wang, Xianshu
AU - Wang, Fengwei
AU - Taniguchi, Ken
AU - Seelan, Ratnam S.
AU - Wang, Liang
AU - Zarfas, Katherine E.
AU - McDonnell, Shannon K.
AU - Qian, Chiping
AU - Pan, Kaifeng
AU - Lu, Youyong
AU - Shridhar, Viji
AU - Couch, Fergus J.
AU - Tindall, Donald J.
AU - Beebe-Dimmer, Jennifer L.
AU - Cooney, Kathleen A.
AU - Isaacs, William B.
AU - Jacobsen, Steven J.
AU - Schaid, Daniel J.
AU - Thibodeau, Stephen N.
AU - Liu, Wanguo
PY - 2006/11/1
Y1 - 2006/11/1
N2 - 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 Arg21insG) 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.
AB - 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 Arg21insG) 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.
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U2 - 10.1158/0008-5472.CAN-06-0638
DO - 10.1158/0008-5472.CAN-06-0638
M3 - Article
C2 - 17079449
AN - SCOPUS:33751304472
SN - 0008-5472
VL - 66
SP - 10302
EP - 10307
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -