Wang Xianshu, Wang Fengwei, Taniguchi Ken, Seelan Ratnam S, Wang Liang, Zarfas Katherine E, McDonnell Shannon K, Qian Chiping, Pan Kaifeng, Lu Youyong, Shridhar Viji, Couch Fergus J, Tindall Donald J, Beebe-Dimmer Jennifer L, Cooney Kathleen A, Isaacs William B, Jacobsen Steven J, Schaid Daniel J, Thibodeau Stephen N, Liu Wanguo
Department of Laboratory Medicine, Mayo Clinic/Mayo Clinical Medical College, Rochester, Minnesota 55905, USA.
Cancer Res. 2006 Nov 1;66(21):10302-7. doi: 10.1158/0008-5472.CAN-06-0638.
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.
几个基因（BRCA1、BRCA2和CHEK2）的种系突变与前列腺癌风险有关，这些基因的产物参与DNA损伤信号通路。为了在该通路中鉴定可能使个体易患这种癌症的其他基因，我们分析了最近鉴定出的一种DNA损伤反应基因p53AIP1（一种编码p53调节的凋亡诱导蛋白1的基因）在前列腺癌中的基因变异。鉴定出五个新的种系变异。在未选择的前列腺肿瘤样本中，发现3%（132例中的4例）存在两种截短变异（Ser(32)Stop和Arg(21)insG）。在另外393例散发性前列腺癌男性中对这两种变异进行基因分型，结果显示频率为3.1%（393例中的12例），而在327例未受影响男性中为0.6%（327例中的2例）（Fisher精确检验，P = 0.018），优势比（OR）为5.1[95%置信区间（95%CI），1.1 - 23.0]。此外，携带截短变异的六个肿瘤中有两个与野生型等位基因的杂合性缺失相关，这表明p53AIP1可能作为一种肿瘤抑制基因发挥作用。我们还表明，截短的p53AIP1在HeLa和COS - 7细胞中无法诱导凋亡和抑制细胞生长。这些结果表明，p53AIP1功能缺失变异与散发性前列腺癌风险相关，并进一步支持了DNA损伤反应基因中的遗传缺陷在前列腺癌发生发展中起重要作用这一概念。
