Background

Tumor mutation burden (TMB) predicts immunotherapy efficacy in solid tumors. However, the biomarker role of TMB is still conflicting in resected tumors. We aimed to examine the association of TMB with prognosis and postoperative chemotherapy (CT) or radiochemotherapy (RCT) efficacy in resected gastric cancer (GC).

Methods

Whole-exome sequencing (WES) was performed in 73 resected GC specimens. Validation cohorts included 352 patients from The Cancer Genome Atlas (TCGA) and 222 patients from the Asian Cancer Research Group (ACRG). Immune infiltration and hypoxia were evaluated by transcriptome data and immunohistochemistry assay.

Results

TMB-high GC had favorable overall survival (OS) and disease-free survival (DFS), but the OS and DFS benefits with postoperative CT/RCT were more pronounced in TMB-low GC. These findings were consistent among all three cohorts and were maintained in the pooled cohort. Stratified by stages in the pooled cohort, stage III GC benefited from postoperative CT/RCT regardless of TMB level while stage Ib/II GC benefited from postoperative CT/RCT in TMB-low but not in TMB-high subgroup. TMB positively correlated with immune infiltration which was characterized by NK cell rather than CD8 + T cell enrichment. TMB-high GC was more hypoxic than TMB-low GC, and TMB-high stage Ib/II GC was the most hypoxic.

Conclusions

High TMB may predict favorable prognosis in resected GC but poor response to postoperative CT/RCT in stage Ib/II subgroup, which may be determined by TMB-associated immune infiltration and hypoxia, respectively.

中文翻译：

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肿瘤突变负荷作为切除胃癌的生物标志物通过其与免疫浸润和缺氧的关联

背景

肿瘤突变负荷 (TMB) 可预测实体瘤的免疫治疗效果。然而，TMB 的生物标志物作用在切除的肿瘤中仍然存在冲突。我们的目的是检查 TMB 与预后和术后化疗 (CT) 或放化疗 (RCT) 在切除胃癌 (GC) 中的疗效的关联。

方法

在 73 个切除的 GC 标本中进行了全外显子组测序 (WES)。验证队列包括来自癌症基因组图谱 (TCGA) 的 352 名患者和来自亚洲癌症研究小组 (ACRG) 的 222 名患者。通过转录组数据和免疫组织化学测定评估免疫浸润和缺氧。

结果

TMB 高 GC 具有良好的总生存期 (OS) 和无病生存期 (DFS)，但术后 CT/RCT 的 OS 和 DFS 获益在 TMB 低 GC 中更为明显。这些发现在所有三个队列中都是一致的，并在合并队列中得以保留。在合并队列中按阶段分层，无论 TMB 水平如何，III 期 GC 都受益于术后 CT/RCT，而 Ib/II 期 GC 在 TMB 低亚组中受益于术后 CT/RCT，但在 TMB 高亚组中没有。TMB 与免疫浸润呈正相关，其特征是 NK 细胞而不是 CD8 + T 细胞富集。TMB-high GC 比 TMB-low GC 更缺氧，并且 TMB-high 阶段 Ib/II GC 最缺氧。

结论

高 TMB 可预测切除 GC 的良好预后，但 Ib/II 期亚组对术后 CT/RCT 反应不佳，这可能分别由 TMB 相关的免疫浸润和缺氧决定。