Objective Intestinal metaplasia (IM) is a premalignant stage that poses a greater risk for subsequent gastric cancer (GC). However, factors regulating IM to GC progression remain unclear. Previously, activated DNA damage response (DDR) signalling factors were shown to engage tumour-suppressive networks in premalignant lesions. Here, we interrogate the relationship of DDR signalling to mutational accumulation in IM lesions. Design IM biopsies were procured from the gastric cancer epidemiology programme, an endoscopic surveillance programme where biopsies have been subjected to (epi)genomic characterisation. IM samples were classified as genome-stable or genome-unstable based on their mutational burden/somatic copy-number alteration (CNA) profiles. Samples were probed for DDR signalling and cell proliferation, using the markers γH2AX and MCM2, respectively. The expression of the gastric stem cell marker, CD44v9, was also assessed. Tissue microarrays representing the GC progression spectrum were included. Results MCM2-positivity increased during GC progression, while γH2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γH2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γH2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γH2AX levels, elevated CD44v9 expression and modest promoter hypermethylation of DNA repair genes WRN, MLH1 and RAD52. Conclusions Our data suggest that IM lesions with active DDR will likely experience a longer latency at the premalignant state until additional hits that override DDR signalling clonally expand and promote progression. These observations provide insights on the factors governing IM progression.

中文翻译：

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DNA损伤信号作为胃肠化生中的抗癌屏障

目的肠上皮化生 (IM) 是一个癌前阶段，对后续胃癌 (GC) 构成更大的风险。然而，调节 IM 到 GC 进展的因素仍不清楚。以前，已显示激活的 DNA 损伤反应 (DDR) 信号因子在癌前病变中参与肿瘤抑制网络。在这里，我们询问了 DDR 信号与 IM 病变中突变积累的关系。设计 IM 活检来自胃癌流行病学计划，这是一项内窥镜监测计划，其中活检已进行（表观）基因组表征。IM 样本根据其突变负荷/体细胞拷贝数改变 (CNA) 谱分为基因组稳定或基因组不稳定。使用标记物 γH2AX 和 MCM2 探测样品的 DDR 信号和细胞增殖，分别。还评估了胃干细胞标志物 CD44v9 的表达。包括代表 GC 进展谱的组织微阵列。结果 MCM2 阳性在 GC 进展期间增加，而 γH2AX 阳性显示从正常到胃炎和 IM 阶段适度增加，GC 进一步增加。γH2AX 水平与慢性炎症的程度相关。有趣的是，基因组稳定的 IM 病变具有更高的 γH2AX 水平，强调了 DDR 信号传导的保护性抗癌作用。相比之下，具有较高突变负荷/CNA 的基因组不稳定 IM 病变具有较低的 γH2AX 水平、升高的 CD44v9 表达和 DNA 修复基因 WRN、MLH1 和 RAD52 的适度启动子高甲基化。结论我们的数据表明，具有活动性 DDR 的 IM 病变可能会在癌前状态下经历更长的潜伏期，直到覆盖 DDR 信号的额外命中克隆扩大并促进进展。这些观察结果提供了关于控制 IM 进展的因素的见解。