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.
DNA damage signalling as an anti-cancer barrier in gastric intestinal
metaplasia
