Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
| العنوان: | Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response |
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| المؤلفون: | Xizeng Mao, Guangchun Han, Namita Shanbhag, Linghua Wang, Ruiping Wang, Guang Peng, Jianhua Zhang, Ying Wang, Shaojun Zhang, Randy L. Johnson, Fatemeh G. Amlashi, Jeannelyn S. Estrella, George A. Calin, Ghia Tatlonghari, Jaffer A. Ajani, Xingzhi Song, Ju Seog Lee, Brian D. Badgwell, Jane Rogers, Sinchita Roy-Chowdhuri, Makoto Kobayashi, Ailing W. Scott, Xiaochuan Dong, Samir M. Hanash, Jian Gu, Melissa Pool Pizzi, Jody Vykoukal, Lang Ma, Irene Thomas, Shumei Song, Zhenning Wang, Longfei Huo, Mariela A. Blum Murphy, Yan Xu, Andrew Futreal, Wei Zhao, Diego Vicente, Kazuto Harada, Jiangkang Jin |
| المصدر: | Gut |
| بيانات النشر: | BMJ, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, DNA Copy Number Variations, gastrointestinal cancer, T cell, cancer genetics, Antineoplastic Agents, Adenocarcinoma, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Stomach Neoplasms, Chromosomal Instability, Exome Sequencing, medicine, Humans, Molecular Targeted Therapy, Exome, Peritoneal Neoplasms, Aged, Aged, 80 and over, Ploidies, biology, Gene Expression Profiling, gastric cancer, Stomach, Gastroenterology, DNA, Neoplasm, Middle Aged, Cell cycle, mutations, Phenotype, Immune checkpoint, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, gene expression, Cancer research, biology.protein, Female, Antibody |
| الوصف: | ObjectivePeritoneal 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.DesignWe 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.ResultsWe identified distinct alterations in PC versus primary GACs, such as more frequentCDH1 and TAF1mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations inTP53, CDH1, TAF1andKMT2C, 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.ConclusionsWe 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. |
| تدمد: | 1468-3288 0017-5749 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::145da6f1ddfcab67847260292cbaa027Test https://doi.org/10.1136/gutjnl-2018-318070Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....145da6f1ddfcab67847260292cbaa027 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14683288 00175749 |
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