title: Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Mayo Clinic/Mayo Clinical Medical College, Rochester, Minnesota 55905, USA.
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Fengwei
authors.initials: F
authors.lastname: Wang
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Ratnam S
authors.initials: RS
authors.lastname: Seelan
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Zarfas
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.forename: Chiping
authors.initials: C
authors.lastname: Qian
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Pan
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Beebe-Dimmer
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jacobsen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
mesh_terms: 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
chemical_list: D051017:Apoptosis Regulatory Proteins; C414742:P53AIP1 protein, human