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Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcr...

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Autores principales: Wang, Ruiping, Song, Shumei, Harada, Kazuto, Ghazanfari Amlashi, Fatemeh, Badgwell, Brian, Pizzi, Melissa Pool, Xu, Yan, Zhao, Wei, Dong, Xiaochuan, Jin, Jiangkang, Wang, Ying, Scott, Ailing, Ma, Lang, Huo, Longfei, Vicente, Diego, Blum Murphy, Mariela, Shanbhag, Namita, Tatlonghari, Ghia, Thomas, Irene, Rogers, Jane, Kobayashi, Makoto, Vykoukal, Jody, Estrella, Jeannelyn Santiano, Roy-Chowdhuri, Sinchita, Han, Guangchun, Zhang, Shaojun, Mao, Xizeng, Song, Xingzhi, Zhang, Jianhua, Gu, Jian, Johnson, Randy L, Calin, George Adrian, Peng, Guang, Lee, Ju-Seog, Hanash, Samir M, Futreal, Andrew, Wang, Zhenning, Wang, Linghua, Ajani, Jaffer A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943252/
https://www.ncbi.nlm.nih.gov/pubmed/31171626
http://dx.doi.org/10.1136/gutjnl-2018-318070
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author Wang, Ruiping
Song, Shumei
Harada, Kazuto
Ghazanfari Amlashi, Fatemeh
Badgwell, Brian
Pizzi, Melissa Pool
Xu, Yan
Zhao, Wei
Dong, Xiaochuan
Jin, Jiangkang
Wang, Ying
Scott, Ailing
Ma, Lang
Huo, Longfei
Vicente, Diego
Blum Murphy, Mariela
Shanbhag, Namita
Tatlonghari, Ghia
Thomas, Irene
Rogers, Jane
Kobayashi, Makoto
Vykoukal, Jody
Estrella, Jeannelyn Santiano
Roy-Chowdhuri, Sinchita
Han, Guangchun
Zhang, Shaojun
Mao, Xizeng
Song, Xingzhi
Zhang, Jianhua
Gu, Jian
Johnson, Randy L
Calin, George Adrian
Peng, Guang
Lee, Ju-Seog
Hanash, Samir M
Futreal, Andrew
Wang, Zhenning
Wang, Linghua
Ajani, Jaffer A
author_facet Wang, Ruiping
Song, Shumei
Harada, Kazuto
Ghazanfari Amlashi, Fatemeh
Badgwell, Brian
Pizzi, Melissa Pool
Xu, Yan
Zhao, Wei
Dong, Xiaochuan
Jin, Jiangkang
Wang, Ying
Scott, Ailing
Ma, Lang
Huo, Longfei
Vicente, Diego
Blum Murphy, Mariela
Shanbhag, Namita
Tatlonghari, Ghia
Thomas, Irene
Rogers, Jane
Kobayashi, Makoto
Vykoukal, Jody
Estrella, Jeannelyn Santiano
Roy-Chowdhuri, Sinchita
Han, Guangchun
Zhang, Shaojun
Mao, Xizeng
Song, Xingzhi
Zhang, Jianhua
Gu, Jian
Johnson, Randy L
Calin, George Adrian
Peng, Guang
Lee, Ju-Seog
Hanash, Samir M
Futreal, Andrew
Wang, Zhenning
Wang, Linghua
Ajani, Jaffer A
author_sort Wang, Ruiping
collection PubMed
description OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
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spelling pubmed-69432522020-01-21 Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response Wang, Ruiping Song, Shumei Harada, Kazuto Ghazanfari Amlashi, Fatemeh Badgwell, Brian Pizzi, Melissa Pool Xu, Yan Zhao, Wei Dong, Xiaochuan Jin, Jiangkang Wang, Ying Scott, Ailing Ma, Lang Huo, Longfei Vicente, Diego Blum Murphy, Mariela Shanbhag, Namita Tatlonghari, Ghia Thomas, Irene Rogers, Jane Kobayashi, Makoto Vykoukal, Jody Estrella, Jeannelyn Santiano Roy-Chowdhuri, Sinchita Han, Guangchun Zhang, Shaojun Mao, Xizeng Song, Xingzhi Zhang, Jianhua Gu, Jian Johnson, Randy L Calin, George Adrian Peng, Guang Lee, Ju-Seog Hanash, Samir M Futreal, Andrew Wang, Zhenning Wang, Linghua Ajani, Jaffer A Gut Stomach OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics. BMJ Publishing Group 2020-01 2019-06-06 /pmc/articles/PMC6943252/ /pubmed/31171626 http://dx.doi.org/10.1136/gutjnl-2018-318070 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. 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
Wang, Ruiping
Song, Shumei
Harada, Kazuto
Ghazanfari Amlashi, Fatemeh
Badgwell, Brian
Pizzi, Melissa Pool
Xu, Yan
Zhao, Wei
Dong, Xiaochuan
Jin, Jiangkang
Wang, Ying
Scott, Ailing
Ma, Lang
Huo, Longfei
Vicente, Diego
Blum Murphy, Mariela
Shanbhag, Namita
Tatlonghari, Ghia
Thomas, Irene
Rogers, Jane
Kobayashi, Makoto
Vykoukal, Jody
Estrella, Jeannelyn Santiano
Roy-Chowdhuri, Sinchita
Han, Guangchun
Zhang, Shaojun
Mao, Xizeng
Song, Xingzhi
Zhang, Jianhua
Gu, Jian
Johnson, Randy L
Calin, George Adrian
Peng, Guang
Lee, Ju-Seog
Hanash, Samir M
Futreal, Andrew
Wang, Zhenning
Wang, Linghua
Ajani, Jaffer A
Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title_full Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title_fullStr Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title_full_unstemmed Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title_short Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
title_sort multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
topic Stomach
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943252/
https://www.ncbi.nlm.nih.gov/pubmed/31171626
http://dx.doi.org/10.1136/gutjnl-2018-318070
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