RT Journal Article SR Electronic T1 DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1738 OP 1749 DO 10.1136/gutjnl-2019-319002 VO 69 IS 10 A1 Vaidehi Krishnan A1 Debbie Xiu En Lim A1 Phuong Mai Hoang A1 Supriya Srivastava A1 Junichi Matsuo A1 Kie Kyon Huang A1 Feng Zhu A1 Khek Yu Ho A1 Jimmy Bok Yan So A1 Christopher Khor A1 Stephen Tsao A1 Ming Teh A1 Kwong Ming Fock A1 Tiing Leong Ang A1 Anand D Jeyasekharan A1 Patrick Tan A1 Khay-Guan Yeoh A1 Yoshiaki Ito YR 2020 UL http://gut.bmj.com/content/69/10/1738.abstract AB 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.