Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk

Xianshu Wang, Fengwei Wang, Ken Taniguchi, Ratnam S. Seelan, Liang Wang, Katherine E. Zarfas, Shannon K. McDonnell, Chiping Qian, Kaifeng Pan, Youyong Lu, Viji Shridhar, Fergus J. Couch, Donald J. Tindall, Jennifer L. Beebe-Dimmer, Kathleen A. Cooney, William B. Isaacs, Steven J. Jacobsen, Daniel J. Schaid, Stephen N. Thibodeau, Wanguo Liu

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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 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.

Original languageEnglish (US)
Pages (from-to)10302-10307
Number of pages6
JournalCancer research
Volume66
Issue number21
DOIs
StatePublished - Nov 1 2006

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, X., Wang, F., Taniguchi, K., Seelan, R. S., Wang, L., Zarfas, K. E., McDonnell, S. K., Qian, C., Pan, K., Lu, Y., Shridhar, V., Couch, F. J., Tindall, D. J., Beebe-Dimmer, J. L., Cooney, K. A., Isaacs, W. B., Jacobsen, S. J., Schaid, D. J., Thibodeau, S. N., & Liu, W. (2006). Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk. Cancer research, 66(21), 10302-10307. https://doi.org/10.1158/0008-5472.CAN-06-0638