Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Int J Cancer. 2014 Sep 15;135(6):1369-80. doi: 10.1002/ijc.28784. Epub 2014 Apr 26.
Despite a multitude of p53 immunohistochemistry (IHC) studies, data on the combined effect of nuclear p53 protein accumulation and TP53 genomic inactivation are lacking for prostate cancer. A tissue microarray including 11,152 prostate cancer samples was analyzed by p53 IHC and fluorescence in situ hybridization. Nuclear p53 accumulation was found in 10.1% of patients including 1.4% with high-level and 8.7% with low-level immunostaining. TP53 sequencing revealed that 17 of 22 (77%) cases with high-level p53 immunostaining, but only 3% (1 of 31) low-level p53 cases carried putative dominant-negative mutations. TP53 deletions occurred in 14.8% of cancers. Both deletions and protein accumulation were linked to unfavorable tumor phenotype and prostate specific antigen (PSA) recurrence (p<0.0001 each). The combination of both methods revealed subgroups with remarkable differences in their clinical course. Tumors with either TP53 deletion (14%) or low-level p53 positivity (8.7%) had identical risks of PSA recurrence, which were markedly higher than in cancers without p53 alterations (p<0.0001). Tumors with both p53 deletion and low-level p53 positivity (1.5%) had a worse prognosis than patients with only one of these alterations (p<0.0001). Tumors with strong p53 immunostaining or homozygous inactivation through deletion of one allele and disrupting translocation involving the second allele had the worst outcome, independent from clinical and pathological parameters. These data demonstrate a differential clinical impact of various TP53 alterations in prostate cancer. Strong p53 immunostaining-most likely accompanying dominant negative or oncogenic p53 mutation-has independent prognostic relevance and may thus represent a clinical useful molecular feature of prostate cancer.
尽管有大量的 p53 免疫组织化学（IHC）研究，但缺乏关于核 p53 蛋白积累和 TP53 基因组失活的综合效应的数据，用于前列腺癌。通过 p53 IHC 和荧光原位杂交分析了包含 11152 例前列腺癌样本的组织微阵列。在 10.1%的患者中发现了核 p53 积累，包括 1.4%为高水平免疫染色和 8.7%为低水平免疫染色。TP53 测序显示，在 22 例高水平 p53 免疫染色的病例中，有 17 例（77%）携带潜在的显性负突变，但仅在 31 例低水平 p53 病例中（3%）发生了突变。14.8%的癌症发生了 TP53 缺失。缺失和蛋白积累都与不良肿瘤表型和前列腺特异性抗原（PSA）复发相关（p<0.0001）。这两种方法的结合揭示了在临床过程中具有显著差异的亚组。有 TP53 缺失（14%）或低水平 p53 阳性（8.7%）的肿瘤 PSA 复发风险相同，明显高于没有 p53 改变的癌症（p<0.0001）。有 p53 缺失和低水平 p53 阳性（1.5%）的肿瘤比只有一种改变的患者预后更差（p<0.0001）。有强 p53 免疫染色或通过缺失一个等位基因和破坏涉及第二个等位基因的易位导致纯合失活的肿瘤，其结果最差，与临床和病理参数无关。这些数据表明在前列腺癌中各种 TP53 改变具有不同的临床影响。强 p53 免疫染色-很可能伴有显性负或致癌 p53 突变-具有独立的预后相关性，因此可能是前列腺癌的一种有用的临床分子特征。
