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.
- gastric metaplasia
- gastric cancer
- DNA damage
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DXEL, PMH and SS contributed equally.
Correction notice This article has been corrected since it published Online First. The fourth author's affiliation details have been amended.
Contributors IHC data acquisition and analysis, DL, PMH, VK and SS; Pathological interpretations and grading of biopsy tissues, SS and MT; Imaging platform and staining optimisation, PMH, VK and ADJ; Mouse data acquisition, JM; Genomic analysis, KKH and PT; Clinical data collection, ZF, JS, CK, ST, KMF and TLA; Data interpretation, VK, SS, ADJ, MT and TI; Drafting and writing manuscript, VK and YI; Revising work, VK, PMH, SS and MT; Conceptualisation and design, YI, YKG and VK; Final approval for publishing work, YKG and YI.
Funding This study was funded by National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme, administered by the Singapore Ministry of Health’s National Medical Research Council.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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