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

Xianshu Wang1, Fengwei Wang, Ken Taniguchi

  • 1Department of Laboratory Medicine, Mayo Clinic/Mayo Clinical Medical College, Rochester, Minnesota 55905, USA.

Cancer Research
|November 3, 2006
PubMed

Insights

Germ line variants in the p53AIP1 gene, involved in DNA damage response, increase prostate cancer risk. Loss-of-function mutations in p53AIP1 may contribute to sporadic prostate cancer development.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Prostate cancer risk is linked to germ line mutations in DNA damage-signaling genes like BRCA1, BRCA2, and CHEK2.
  • Identifying additional susceptibility genes within this pathway is crucial for understanding prostate cancer etiology.

Purpose of the Study:

  • To investigate the role of the DNA damage-response gene p53AIP1 (p53-regulated apoptosis-inducing protein 1) in prostate cancer susceptibility.
  • To identify and characterize novel germ line variants of p53AIP1 in prostate cancer patients.

Main Methods:

  • Analysis of germ line DNA for p53AIP1 variants in prostate cancer patients and controls.
  • Genotyping of identified variants in larger cohorts.
  • Functional assays in cell lines to assess the impact of truncated p53AIP1 on apoptosis and cell growth.

Main Results:

  • Five novel germ line variants in p53AIP1 were identified, including two truncating variants (Ser(32)Stop and Arg(21)insG).
  • Truncating p53AIP1 variants were found at a significantly higher frequency in sporadic prostate cancer patients (3.1%) compared to controls (0.6%), yielding an odds ratio of 5.1.
  • Loss of heterozygosity for wild-type p53AIP1 alleles was observed in tumors with truncating variants, and truncated p53AIP1 failed to induce apoptosis or suppress cell growth in functional assays.

Conclusions:

  • Loss-of-function variants in p53AIP1 are associated with an increased risk of sporadic prostate cancer.
  • These findings highlight the importance of DNA damage-response gene defects in prostate cancer development and suggest p53AIP1 may function as a tumor suppressor.

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