Please use this identifier to cite or link to this item: https://doi.org/10.1136/gutjnl-2019-319002
Title: DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
Authors: Krishnan, Vaidehi 
Lim, Debbie Xiu En 
Hoang, Phuong Mai 
Srivastava, Supriya 
Matsuo, Junichi 
Huang, Kie Kyon 
Zhu, Feng 
Ho, Khek Yu 
So, Jimmy Bok Yan 
Khor, Christopher 
Tsao, Stephen
Teh, Ming 
Fock, Kwong Ming 
Ang, Tiing Leong 
Jeyasekharan, Anand D 
Tan, Patrick 
Yeoh, Khay-Guan 
Ito, Yoshiaki 
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
gastric metaplasia
gastric cancer
DNA damage
ONCOGENE-INDUCED SENESCENCE
CONSTITUTIVE ACTIVATION
CANCER-CELLS
STEM-CELLS
EXPRESSION
STOMACH
MARKER
RISK
REPLICATION
PROGRESSION
Issue Date: 1-Oct-2020
Publisher: BMJ PUBLISHING GROUP
Citation: Krishnan, Vaidehi, Lim, Debbie Xiu En, Hoang, Phuong Mai, Srivastava, Supriya, Matsuo, Junichi, Huang, Kie Kyon, Zhu, Feng, Ho, Khek Yu, So, Jimmy Bok Yan, Khor, Christopher, Tsao, Stephen, Teh, Ming, Fock, Kwong Ming, Ang, Tiing Leong, Jeyasekharan, Anand D, Tan, Patrick, Yeoh, Khay-Guan, Ito, Yoshiaki (2020-10-01). DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia. GUT 69 (10) : 1738-1749. ScholarBank@NUS Repository. https://doi.org/10.1136/gutjnl-2019-319002
Abstract: © 2020 BMJ Publishing Group. All rights reserved. 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 γ3H2AX 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 γ3H2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γ3H2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γ3H2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γ3H2AX 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.
Source Title: GUT
URI: https://scholarbank.nus.edu.sg/handle/10635/184183
ISSN: 00175749
14683288
DOI: 10.1136/gutjnl-2019-319002
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