Background

In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown.

Methods

We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed.

Results

Eighteen patients (aged 29–78 years) with DGCs and nine normal subjects (28–77 years) were examined. The mutation burden in intramucosal DGCs (10–66 mutations per exome) from individuals aged 29–73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2–5 years showed no progression.

Conclusions

Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

中文翻译：

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CDH1突变未感染的幽门螺杆菌黏膜内印戒细胞癌的惰性特征

背景

据报道，在未感染幽门螺杆菌( Hp ) 的个体中，弥漫型胃癌 (DGC) 是最常见的癌症类型。然而，未感染Hp的散发性 DGC 的致癌机制在很大程度上是未知的。

方法

我们对未感染Hp的DGC 和未感染Hp的正常胃黏膜进行了全外显子组测序。对于高级 DGC，还分析了外部数据集。

结果

检查了 18 名 DGC 患者（年龄 29-78 岁）和 9 名正常受试者（28-77 岁）。来自 29-73 岁个体的黏膜内 DGCs（每个外显子组 10-66 个突变）的突变负荷与正常胃腺体中的突变负荷没有太大差异，后者显示出恒定的突变积累率（0.33 个突变/外显子组/年）。无偏 dN/dS 分析表明CDH1体细胞突变是黏膜内 DGC 的驱动突变。CDH1突变在黏膜内 DGC (67%) 中比在晚期 DGC (27%) 中更常见。相比之下，TP53突变在晚期 DGC (52%) 中比在粘膜内 DGC (0%) 中更频繁。这种突变差异表明CDH1-突变的粘膜内 DGCs 对晚期 DGC 形成的贡献相对较小。在 16 个黏膜内 DGC（中位大小，6.5 mm）中，15 个 DGC 是纯印戒细胞癌（SRCC），E-cadherin 表达降低，增殖能力低（中位 Ki-67 指数，2.4%）。在 2-5 年内通过内镜检查的 5 个 SRCC 没有进展。

结论

由于CDH1突变导致的 E-cadherin 功能受损被认为是Hp未感染的粘膜内 SRCC 的早期致癌事件。遗传和临床分析表明，未感染Hp的黏膜内 SRCC 可能不太可能发展成晚期 DGC。