Background Spasmolytic polypeptide-expressing metaplasia (SPEM) is present in more than 90% of resected gastric cancer tissues. However, although widely regarded as a pre-cancerous tissue, its genetic characteristics have not been well studied. Methods Immunohistochemistry using Trefoil factor 2 (TFF2) antibodies was used to identify TFF2-positive SPEM cells within SPEM glands in the stomach of Helicobacter felis (H. felis) -infected mice and human clinical samples. Laser microdissection was used to isolate specific cells from both the infected mice and the human samples. The genetic instability in these cells was examined by measuring the lengths of microsatellite (MS) markers using capillary electrophoresis. Also, genome-wide genetic variations in the SPEM cells from the clinical sample was examined using deep whole-exome sequencing. Results SPEM cells indeed exhibit not only heightened MS instability (MSI), but also genetic instabilities that extend genome-wide. Furthermore, surprisingly, we found that morphologically normal, TFF2-negative cells also contain a comparable degree of genomic instabilities as the co-resident SPEM cells within the SPEM glands. Conclusion These results, for the first time, clearly establish elevated genetic instability as a critical property of SPEM glands, which may provide a greater possibility for malignant clone selection. More importantly, these results indicate that SPEM cells may not be the sole origin of carcinogenesis in the stomach and strongly suggest the common progenitor of these cells, the stem cells, as the source of these genetic instabilities, and thus, potential key players in carcinogenesis.

中文翻译：

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癌前痉挛性表达胃腺的遗传不稳定性增强的证据。

背景表达痉挛性多肽的化生（SPEM）存在于超过90％的切除的胃癌组织中。然而，尽管被广泛认为是癌前组织，但其遗传特性尚未得到很好的研究。方法使用三叶因子2（TFF2）抗体进行免疫组织化学，以鉴定感染了猫幽门螺杆菌（H. felis）的小鼠和人类临床样品中SPEM腺内TFF2阳性的SPEM细胞。激光显微切割用于从受感染的小鼠和人类样品中分离特异性细胞。通过使用毛细管电泳测量微卫星（MS）标记的长度来检查这些细胞的遗传不稳定性。此外，使用深度全外显子组测序检查了来自临床样品的SPEM细胞中的全基因组遗传变异。结果SPEM细胞确实不仅表现出更高的MS不稳定性（MSI），而且还表现出在整个基因组范围内扩展的遗传不稳定性。此外，令人惊讶的是，我们发现形态正常的TFF2阴性细胞也含有与SPEM腺体内共存SPEM细胞相当程度的基因组不稳定性。结论这些结果首次清楚地表明，遗传不稳定性升高是SPEM腺的关键特性，这可能为恶性克隆选择提供更大的可能性。更重要的是，这些结果表明SPEM细胞可能不是胃癌发生的唯一来源，并强烈暗示了这些细胞的共同祖细胞干细胞是这些遗传不稳定性的来源，因此可能是癌发生的潜在关键参与者。