背景:许多研究表明p53过表达与胃癌患者生存率降低之间存在相关性。然而,存在矛盾的发现,我们假设这些差异来自癌症的复杂性和异质性,再加上对p53异常表达缺乏共识。
方法:我们招募了187例胃癌手术切除患者。患者分类基于EB病毒(EBV),微卫星不稳定性(MSI),和劳伦分类(肠道,扩散和混合)。利用增量算法,我们评估了所有187例的p53免疫组织化学(IHC)模式,而对152例病例成功进行了下一代测序以鉴定TP53突变(mutTP53).
结果:在152例中32%的患者中发现了MutTP53,包括36个错觉,5废话,和7个移码改动。错义突变主要与p53过表达相关,而与null表达式相关的废话和移码变化。试验计算表明,无效表达和>40%的p53IHC截止值提供了mutTP53的最佳预测(kappa系数,0.427),在弥漫型中观察到最高的一致性(0.524),在肠型中观察到最低的一致性(0.269)。零表达和p53IHC截止值>10%,但不是mutTP53本身,提供了生存结果的最佳预测(p=0.043),特别是在扩散型(p=0.044)。多因素分析显示,p53IHC异常表达不是独立的预后因素。
结论:P53IHC模式是mutTP53和胃癌预后的预测性生物标志物,其中先决条件涉及考虑截止值和分子组织学亚型的细微差别方法。
BACKGROUND: Numerous studies have demonstrated a correlation between p53 overexpression and diminished survival in gastric cancer patients. However, conflicting findings exist, and we hypothesize that these discrepancies arise from the cancer\'s complexity and heterogeneity, coupled with a lack of consensus on aberrant p53 expression.
METHODS: We enrolled a cohort of 187 patients with surgically resected gastric cancer. Patient categorization was based on Epstein-Barr virus (EBV), microsatellite instability (MSI), and Lauren classification (intestinal, diffuse and mixed). Utilizing an incremental algorithm, we evaluated p53 immunohistochemical (IHC) patterns in all 187 cases, while next-generation sequencing was successfully performed on 152 cases to identify TP53 mutations (mutTP53).
RESULTS: MutTP53 was identified in 32 % of the 152 cases, comprising 36 missense, 5 nonsense, and 7 frameshift alterations. Missense mutations predominantly correlated with p53 overexpression, while nonsense and frameshifting alterations related to null expression. Trial calculations indicated that null expression and a p53 IHC cutoff at >40 % offered the best prediction of mutTP53 (kappa coefficient, 0.427), with the highest agreement (0.524) observed in diffuse type and the lowest (0.269) in intestinal type. Null expression and a p53 IHC cutoff at >10 %, but not mutTP53 per se, provided the optimal prediction of survival outcome (p = 0.043), particularly in diffuse type (p = 0.044). Multivariate analysis showed that aberrant p53 IHC expression was not an independent prognostic factor.
CONCLUSIONS: P53 IHC patterns are predictive biomarkers for mutTP53 and gastric cancer outcomes, where a prerequisite involves a nuanced approach considering cutoff values and molecular-histologic subtyping.