Please use this identifier to cite or link to this item: https://doi.org/10.1136/gutjnl-2019-319002
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dc.titleDNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
dc.contributor.authorKrishnan, Vaidehi
dc.contributor.authorLim, Debbie Xiu En
dc.contributor.authorHoang, Phuong Mai
dc.contributor.authorSrivastava, Supriya
dc.contributor.authorMatsuo, Junichi
dc.contributor.authorHuang, Kie Kyon
dc.contributor.authorZhu, Feng
dc.contributor.authorHo, Khek Yu
dc.contributor.authorSo, Jimmy Bok Yan
dc.contributor.authorKhor, Christopher
dc.contributor.authorTsao, Stephen
dc.contributor.authorTeh, Ming
dc.contributor.authorFock, Kwong Ming
dc.contributor.authorAng, Tiing Leong
dc.contributor.authorJeyasekharan, Anand D
dc.contributor.authorTan, Patrick
dc.contributor.authorYeoh, Khay-Guan
dc.contributor.authorIto, Yoshiaki
dc.date.accessioned2020-11-27T08:25:57Z
dc.date.available2020-11-27T08:25:57Z
dc.date.issued2020-10-01
dc.identifier.citationKrishnan, 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
dc.identifier.issn00175749
dc.identifier.issn14683288
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/184183
dc.description.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.
dc.language.isoen
dc.publisherBMJ PUBLISHING GROUP
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectGastroenterology & Hepatology
dc.subjectgastric metaplasia
dc.subjectgastric cancer
dc.subjectDNA damage
dc.subjectONCOGENE-INDUCED SENESCENCE
dc.subjectCONSTITUTIVE ACTIVATION
dc.subjectCANCER-CELLS
dc.subjectSTEM-CELLS
dc.subjectEXPRESSION
dc.subjectSTOMACH
dc.subjectMARKER
dc.subjectRISK
dc.subjectREPLICATION
dc.subjectPROGRESSION
dc.typeArticle
dc.date.updated2020-11-27T06:26:42Z
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentMEDICINE
dc.contributor.departmentPATHOLOGY
dc.contributor.departmentPHYSIOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1136/gutjnl-2019-319002
dc.description.sourcetitleGUT
dc.description.volume69
dc.description.issue10
dc.description.page1738-1749
dc.published.statePublished
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