Hypothesis: 

Poorly cohesive (PC) gastric cancer (GC) exhibits variable clinical behavior, being extremely aggressive in most cases but more indolent at times. We hypothesized that the integrative genomic and gene expression characterization of a PC GC series could help identifying molecular subtypes with potential clinical implications.

Materials and Methods: 

64 PC GCs were assessed for alterations in 409 genes and 30 cases were subjected to transcriptomic profiling of 20,815 genes.

Results: 

A median of 8.2 mutations per Mb (interquartile range 6.9–10.4) was found and a tumor mutational load >10 muts/Mb was significantly associated with patients’ worse survival (P=0.0024). The most frequent mutated genes were CDH1 and TP53 (each 32.8%) followed by PIK3CA (10.9%). In 15 samples (23.4%), at least 1 chromatin remodeling gene was mutated: KMT2D (5 cases); ARID1A and BAP1 (4 cases each); EZH2, KMT2A, PBRM1 (1 case each). Eight samples (12.5%) had fusion genes involving CLDN18 gene. Gene expression profiling identified 4 different clusters: cluster A associated with epithelial to mesenchymal transition (EMT) signature; cluster B associated to proliferative signature and EMT; cluster C correlated to hedgehog signaling; cluster D showing no enrichment for any of the previous signatures. Notably, cluster A and B showed a worse prognosis compared with clusters C and D (P=0.0095).

Conclusion: 

integrated genomic and transcriptomic analysis suggest the existence of 4 molecular subtypes of PC GC with prognostic significance where EMT features are associated with a worse outcome.

中文翻译：

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表现出上皮-间充质转化的转录组特征的粘性差的胃癌表现出积极的行为

假设： 

内聚性差的 (PC) 胃癌 (GC) 表现出多变的临床行为，在大多数情况下极具侵袭性，但有时更为惰性。我们假设 PC GC 系列的综合基因组和基因表达表征可以帮助识别具有潜在临床意义的分子亚型。

材料和方法： 

评估了 64 个 PC GC 的 409 个基因的改变，并对 30 个病例进行了 20,815 个基因的转录组分析。

结果： 

发现每 Mb 有 8.2 个突变的中位数（四分位距 6.9-10.4），肿瘤突变负荷 >10 muts/Mb 与患者较差的生存率显着相关（P = 0.0024）。最常见的突变基因是CDH1和TP53（各 32.8%），其次是PIK3CA（10.9%）。15个样本（23.4%）中至少有1个染色质重塑基因发生突变：KMT2D（5例）；ARID1A和BAP1（各 4 例）；EZH2、KMT2A、PBRM1（各 1 箱）。8 个样本 (12.5%) 具有涉及CLDN18的融合基因基因。基因表达谱确定了 4 个不同的簇：簇 A 与上皮间质转化 (EMT) 特征相关；与增殖特征和 EMT 相关的簇 B；簇 C 与刺猬信号相关；集群 D 显示没有任何先前签名的富集。值得注意的是，与集群 C 和 D 相比，集群 A 和 B 的预后更差（P = 0.0095）。

结论： 

综合基因组和转录组分析表明存在 4 种具有预后意义的 PC GC 分子亚型，其中 EMT 特征与较差的结果相关。