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

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 netw...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497583/
https://www.ncbi.nlm.nih.gov/pubmed/31937549
http://dx.doi.org/10.1136/gutjnl-2019-319002
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author 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
author_facet 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
author_sort Krishnan, Vaidehi
collection PubMed
description 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.
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spelling pubmed-74975832020-09-28 DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia 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 Gut Stomach 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. BMJ Publishing Group 2020-10 2020-01-14 /pmc/articles/PMC7497583/ /pubmed/31937549 http://dx.doi.org/10.1136/gutjnl-2019-319002 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Stomach
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
DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title_full DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title_fullStr DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title_full_unstemmed DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title_short DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
title_sort dna damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
topic Stomach
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497583/
https://www.ncbi.nlm.nih.gov/pubmed/31937549
http://dx.doi.org/10.1136/gutjnl-2019-319002
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