Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations
Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations
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DOI：
10.1007/s10120-021-01191-8
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发表时间：
2021-05-07
期刊：
影响因子：
7.4
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
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作者：
Nikaido, Mitsuhiro;Kakiuchi, Nobuyuki;Seno, Hiroshi
背景在幽门螺杆菌（Hp）未感染的个体中，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。方法采用全外显子测序技术对Hp感染的正常胃粘膜和未感染Hp的DGCs进行测序。对于晚期DGC，还分析了外部数据集。结果18例DGC患者（年龄29-78岁）和9例正常人（年龄28-77岁）进行了超声心动图检查。来自29-73岁个体的粘膜内DGC中的突变负荷（每个外显子组10-66个突变）与正常胃腺中的突变负荷没有很大差异，正常胃腺显示恒定的突变累积率（0.33个突变/外显子组/年）。无偏dN/dS分析表明，CDH 1体细胞突变是粘膜内DGC的驱动突变。CDH 1突变在粘膜内DGC（67%）中比在进展期DGC（27%）中更常见。相反，TP 53突变在晚期DGC中（52%）比在粘膜内DGC中（0%）更频繁。这种突变的差异表明，CDH 1突变的粘膜内DGC对晚期DGC形成的贡献相对较小。在16例粘膜内DGC（中位大小为6.5 mm）中，15例DGC为纯印戒细胞癌（SRCC），E-钙粘蛋白表达减少，增殖能力低（中位Ki-67指数为2.4%）。在2-5年内通过内窥镜审查的5例SRC显示无进展。结论CDH 1突变导致的E-cadherin功能受损可能是Hp未感染黏膜内SRCC的早期致癌事件。遗传和临床分析表明，Hp未感染的粘膜内SRCC可能不太可能发展为晚期DGC。
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.