Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer
Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer
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DOI：
10.1002/ijc.28784
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发表时间：
2014-09-15
影响因子：
6.4
通讯作者：
Schlomm, Thorsten
中科院分区：
文献类型：
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作者：
Kluth, Martina;Harasimowicz, Silvia;Schlomm, Thorsten
尽管有大量的p53免疫组织化学（IHC）的研究，核p53蛋白积累和TP53基因组失活的综合作用的数据是缺乏前列腺癌。通过p53 IHC和荧光原位杂交分析了包括11，152个前列腺癌样本的组织微阵列。10.1%的患者发现细胞核p53积聚，其中1.4%为高水平免疫染色，8.7%为低水平免疫染色。TP53测序显示，22例（77%）高水平p53免疫染色的病例中有17例，但只有3%（31例）低水平p53病例携带推定的显性阴性突变。TP53缺失发生在14.8%的癌症中。缺失和蛋白质积累都与不利的肿瘤表型和前列腺特异性抗原（PSA）复发有关（p < 0.0001）。这两种方法的结合揭示了亚组在临床过程中的显着差异。TP53缺失（14%）或低水平p53阳性（8.7%）的肿瘤具有相同的PSA复发风险，显著高于无p53改变的癌症（p < 0.0001）。p53缺失和低水平p53阳性（1.5%）的肿瘤比只有其中一种改变的患者预后更差（p < 0.0001）。肿瘤与强p53免疫染色或纯合失活，通过删除一个等位基因和破坏易位涉及第二个等位基因有最差的结果，独立于临床和病理参数。这些数据证明了前列腺癌中各种TP53改变的不同临床影响。强p53免疫染色最有可能伴随显性阴性或致癌p53突变具有独立的预后相关性，因此可能代表前列腺癌的临床有用的分子特征。
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.