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PIK3CA and KRAS Amplification in Esophageal Adenocarcinoma and their Impact on the Inflammatory Tumor Microenvironment and Prognosis.

食管腺癌中 PIK3CA 和 KRAS 扩增及其对炎性肿瘤微环境和预后的影响。

  • 影响因子:3.30
  • DOI:10.1016/j.tranon.2019.10.013
  • 作者列表:"Essakly A","Loeser H","Kraemer M","Alakus H","Chon SH","Zander T","Buettner R","Hillmer AM","Bruns CJ","Schroeder W","Gebauer F","Quaas A
  • 发表时间:2020-02-01
Abstract

:Gene amplifications of PIK3CA or KRAS induce a downstream activation of the AKT-mTOR or RAF-ERK-pathways. Interactions of the active AKT pathway have been implicated in the inflammatory tumor microenvironment. Nothing is known about these interactions or prognostic power in esophageal adenocarcinoma (EAC). We retrospectively analyzed a large cohort of 685 EAC considering KRAS and PIK3CA gene amplification using fluorescence in situ hybridization (FISH) and immunohistochemistry. These results were correlated with clinical and molecular data as well as the inflammatory tumor microenvironment. Amplifications of KRAS were seen in 94 patients (17.1%), PIK3CA amplifications in 23 patients (5.0%). KRAS amplifications significantly correlated with nodal positive patients and poorer overall survival (OS) in the subgroup without neoadjuvant treatment (p = 0.004), coamplifications of Her2 (p = 0.027), and TP53 mutations (p = 0.016). PIK3CA amplifications significantly correlated with a high amount of tumor infiltrating T cells (p = 0.003) and showed a tendency to better OS (p = 0.068). A correlation with checkpoint makers (PD-L1, LAG3, VISTA, TIM3, IDO) could not be revealed. Our findings are the first to link the KRAS amplified genotype with lymphonodal positivity and poor prognosis and the PIK3CA-amplified genotype with a T cell-rich microenvironment in EAC. Future studies must show whether these two genotype subgroups can be therapeutically influenced. A dual inhibition of MEK and SHP2T could be effective in the subgroup of KRAS amplified EACs and an immune checkpoint blockade may prove to be particularly promising in the subgroup of PIK3CA-amplified EACs.

摘要

: PIK3CA 或 KRAS 的基因扩增诱导 AKT-mTOR 或 RAF-ERK-通路的下游激活。活性 AKT 通路的相互作用与炎症肿瘤微环境有关。关于这些相互作用或食管腺癌 (EAC) 的预后能力一无所知。我们使用荧光原位杂交 (FISH) 和免疫组织化学回顾性分析了考虑 KRAS 和 PIK3CA 基因扩增的 685 个 EAC 的大型队列。这些结果与临床和分子数据以及炎症肿瘤微环境相关。KRAS 扩增 94 例 (17.1%),PIK3CA 扩增 23 例 (5.0%)。KRAS 扩增与无新辅助治疗 (p = 0.004) 、 Her2 共扩增 (p = 0.027) 亚组中淋巴结阳性患者和总生存期 (OS) 较差显著相关, 和 TP53 突变 (p = 0.016)。PIK3CA 扩增与大量肿瘤浸润 T 细胞显著相关 (p = 0.003),并显示出更好的 OS 趋势 (p = 0.068)。无法揭示与检查点制造商 (PD-L1 、 LAG3 、 VISTA 、 TIM3 、 IDO) 的相关性。我们的研究结果首次将 KRAS 扩增基因型与淋巴结阳性和不良预后联系起来,将 PIK3CA-amplified 基因型与 EAC 中富含 T 细胞的微环境联系起来。未来的研究必须表明这两个基因型亚组是否可以受到治疗影响。MEK 和 SHP2T 的双重抑制可能对 KRAS 扩增的 EACs 亚组有效,免疫检查点阻断可能被证明在 PIK3CA-amplified EACs 亚组中特别有前途。

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