Background

Gastric cancer (GC) has been classified based on molecular profiling like The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG), and attempts have been made to establish therapeutic strategies based on these classifications. However, it is difficult to predict the survival according to these classifications especially in radically resected patients. We aimed to establish a new molecular classification of GC which predicts the survival in patients undergoing radical gastrectomy.

Methods

The present study included 499 Japanese patients with advanced GC undergoing radical (R0/R1) gastrectomy. Whole-exome sequencing, panel sequencing, and gene expression profiling were conducted (High-tech Omics-based Patient Evaluation [Project HOPE]). We classified patients according to TCGA and ACRG subtypes, and evaluated the clinicopathologic features and survival. Then, we attempted to classify patients according to their molecular profiles associated with biological features and survival (HOPE classification).

Results

TCGA and ACRG classifications failed to predict the survival. In HOPE classification, hypermutated (HMT) tumors were selected first as a distinctive feature, and T-cell-inflamed expression signature-high (TCI) tumors were then extracted. Finally, the remaining tumors were divided by the epithelial-mesenchymal transition (EMT) expression signature. HOPE classification significantly predicted the disease-specific and overall survival (p < 0.001 and 0.020, respectively). HMT + TCI showed the best survival, while EMT-high showed the worst survival. The HOPE classification was successfully validated in the TCGA cohort.

Conclusions

We established a new molecular classification of gastric cancer that predicts the survival in patients undergoing radical surgery.

中文翻译：

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基于HOPE项目的胃癌分子分类预测根治性胃切除术患者的生存率

背景

胃癌 (GC) 已根据分子谱进行分类，如癌症基因组图谱 (TCGA) 和亚洲癌症研究小组 (ACRG)，并已尝试根据这些分类建立治疗策略。然而，根据这些分类很难预测生存率，尤其是在根治性切除的患者中。我们旨在建立一种新的 GC 分子分类，以预测接受根治性胃切除术的患者的生存率。

方法

本研究包括 499 名接受根治性 (R0/R1) 胃切除术的日本晚期胃癌患者。进行了全外显子组测序、面板测序和基因表达谱分析（基于高科技组学的患者评估 [Project HOPE]）。我们根据 TCGA 和 ACRG 亚型对患者进行分类，并评估临床病理特征和生存率。然后，我们尝试根据与生物学特征和生存相关的分子特征对患者进行分类（HOPE 分类）。

结果

TCGA 和 ACRG 分类未能预测生存。在 HOPE 分类中，首先选择超突变 (HMT) 肿瘤作为显着特征，然后提取 T 细胞发炎的高表达 (TCI) 肿瘤。最后，剩余的肿瘤除以上皮间质转化 (EMT) 表达特征。HOPE 分类显着预测疾病特异性和总生存率（ 分别为p < 0.001 和 0.020）。HMT + TCI 显示出最好的存活率，而 EMT-high 显示出最差的存活率。HOPE 分类在 TCGA 队列中得到了成功验证。

结论

我们建立了一种新的胃癌分子分类，可预测接受根治性手术的患者的生存率。