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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 |
Appears in Collections: | Staff Publications Elements |
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