计算机断层扫描检测到的外膜静脉侵犯相关基因特征：胃癌患者免疫检查点抑制剂治疗的潜在阴性生物标志物。
Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer.
机构信息
Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Radiology, Peking University People's Hospital, 11 Xizhimen South St., Beijing, 100044, China.
出版信息
J Transl Med. 2023 Jan 5;21(1):4. doi: 10.1186/s12967-022-03845-2.
BACKGROUND
To investigate the association between computed tomography (CT)-detected extramural venous invasion (EMVI)-related genes and immunotherapy resistance and immune escape in patients with gastric cancer (GC).
METHODS
Thirteen patients with pathologically proven locally advanced GC who had undergone preoperative abdominal contrast-enhanced CT and radical resection surgery were included in this study. Transcriptome sequencing was multidetector performed on the cancerous tissue obtained during surgery, and EMVI-related genes (P value for association < 0.001) were selected. A single-sample gene set enrichment analysis algorithm was also used to divide all GC samples (n = 377) in The Cancer Genome Atlas (TCGA) database into high and low EMVI-immune related groups based on immune-related differential genes. Cluster analysis was used to classify EMVI-immune-related genotypes, and survival among patients was validated in TCGA and Gene Expression Omnibus (GEO) cohorts. The EMVI scores were calculated using principal component analysis (PCA), and GC samples were divided into high and low EMVI score groups. Microsatellite instability (MSI) status, tumor mutation burden (TMB), response rate to immune checkpoint inhibitors (ICIs), immune escape were compared between the high and low EMVI score groups. Hub gene of the model in pan-cancer analysis was also performed.
RESULTS
There were 17 EMVI-immune-related genes used for cluster analysis. PCA identified 8 genes (PCH17, SEMA6B, GJA4, CD34, ACVRL1, SOX17, CXCL12, DYSF) that were used to calculate EMVI scores. High EMVI score groups had lower MSI, TMB and response rate of ICIs, status but higher immune escape status. Among the 8 genes used for EMVI scores, CXCL12 and SOX17 were at the core of the protein-protein interaction (PPI) network and had a higher priority in pan-cancer analysis. Immunohistochemical analysis showed that the expression of CXCL12 and SOX17 was significantly higher in CT-detected EMVI-positive samples than in EMVI-negative samples (P < 0.0001).
CONCLUSION
A CT-detected EMVI gene signature could be a potential negative biomarker for ICIs treatment, as the signature is negatively correlated with TMB, and MSI, resulting in poorer prognosis.
背景
为了研究计算机断层扫描（CT）检测到的壁外静脉侵犯（EMVI）相关基因与胃癌（GC）患者免疫治疗耐药和免疫逃逸之间的关系。
方法
本研究纳入了 13 名经病理证实的局部晚期 GC 患者，这些患者术前均进行了腹部增强 CT 检查和根治性手术。对手术获得的癌组织进行多排螺旋 CT 转录组测序，并选择与 EMVI 相关的基因（关联 P 值<0.001）。还使用单样本基因集富集分析算法，根据免疫相关差异基因，将 TCGA 数据库中的所有 GC 样本（n=377）分为高和低 EMVI 免疫相关组。基于 EMVI 免疫相关基因型进行聚类分析，并在 TCGA 和 GEO 队列中验证患者的生存情况。使用主成分分析（PCA）计算 EMVI 评分，并根据 EMVI 评分将 GC 样本分为高和低 EMVI 评分组。比较高和低 EMVI 评分组之间的微卫星不稳定性（MSI）状态、肿瘤突变负荷（TMB）、免疫检查点抑制剂（ICIs）反应率、免疫逃逸情况。还对泛癌分析中的模型的枢纽基因进行了分析。
结果
进行聚类分析时使用了 17 个 EMVI 免疫相关基因。PCA 鉴定出 8 个基因（PCH17、SEMA6B、GJA4、CD34、ACVRL1、SOX17、CXCL12、DYSF），用于计算 EMVI 评分。高 EMVI 评分组的 MSI、TMB 和 ICIs 反应率较低，但免疫逃逸状态较高。在用于 EMVI 评分的 8 个基因中，CXCL12 和 SOX17 是蛋白质-蛋白质相互作用（PPI）网络的核心，在泛癌分析中具有更高的优先级。免疫组织化学分析显示，在 CT 检测到的 EMVI 阳性样本中，CXCL12 和 SOX17 的表达明显高于 EMVI 阴性样本（P<0.0001）。
结论
CT 检测到的 EMVI 基因特征可能是 ICIs 治疗的潜在负性生物标志物，因为该特征与 TMB 和 MSI 呈负相关，导致预后较差。
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