RGD Reference Report - Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma. - Rat Genome Database

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Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

Authors: Hao, Dapeng  He, Siyuan  Harada, Kazuto  Pizzi, Melissa Pool  Lu, Yang  Guan, Pujun  Chen, Lu  Wang, Ruiping  Zhang, Shaojun  Sewastjanow-Silva, Matheus  Abdelhakeem, Ahmed  Shanbhag, Namita  Bhutani, Manoop  Han, Guangchun  Lee, Jeffrey H  Zhao, Shuangtao  Weston, Brian  Blum Murphy, Mariela  Waters, Rebecca  Estrella, Jeannelyn Santiano  Roy-Chowdhuri, Sinchita  Gan, Qiong  Lee, Ju-Seog  Peng, Guang  Hanash, Samir M  Calin, George Adrian  Song, Xingzhi  Zhang, Jianhua  Song, Shumei  Wang, Linghua  Ajani, Jaffer A 
Citation: Hao D, etal., Gut. 2021 Nov;70(11):2055-2065. doi: 10.1136/gutjnl-2020-322707. Epub 2020 Dec 17.
RGD ID: 151356972
Pubmed: PMID:33334899   (View Abstract at PubMed)
DOI: DOI:10.1136/gutjnl-2020-322707   (Journal Full-text)


OBJECTIVE: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.
DESIGN: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.
RESULTS: KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.
CONCLUSION: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MAP3K13Humangastroesophageal adenocarcinoma  HEP  RGD 
Map3k13Ratgastroesophageal adenocarcinoma  ISOMAP3K13 (Homo sapiens) RGD 
Map3k13Mousegastroesophageal adenocarcinoma  ISOMAP3K13 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k13  (mitogen-activated protein kinase kinase kinase 13)

Genes (Mus musculus)
Map3k13  (mitogen-activated protein kinase kinase kinase 13)

Genes (Homo sapiens)
MAP3K13  (mitogen-activated protein kinase kinase kinase 13)


Additional Information