TY - JOUR
T1 - Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma
AU - Hao, Dapeng
AU - He, Siyuan
AU - Harada, Kazuto
AU - Pizzi, Melissa Pool
AU - Lu, Yang
AU - Guan, Pujun
AU - Chen, Lu
AU - Wang, Ruiping
AU - Zhang, Shaojun
AU - Sewastjanow-Silva, Matheus
AU - Abdelhakeem, Ahmed
AU - Shanbhag, Namita
AU - Bhutani, Manoop
AU - Han, Guangchun
AU - Lee, Jeffrey H.
AU - Zhao, Shuangtao
AU - Weston, Brian
AU - Blum Murphy, Mariela
AU - Waters, Rebecca
AU - Estrella, Jeannelyn Santiano
AU - Roy-Chowdhuri, Sinchita
AU - Gan, Qiong
AU - Lee, Ju Seog
AU - Peng, Guang
AU - Hanash, Samir M.
AU - Calin, George Adrian
AU - Song, Xingzhi
AU - Zhang, Jianhua
AU - Song, Shumei
AU - Wang, Linghua
AU - Ajani, Jaffer A.
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - Gastric adenocarcinoma
KW - Oesophageal cancer
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U2 - 10.1136/gutjnl-2020-322707
DO - 10.1136/gutjnl-2020-322707
M3 - Article
C2 - 33334899
AN - SCOPUS:85098211175
SN - 0017-5749
VL - 70
SP - 2055
EP - 2065
JO - Gut
JF - Gut
IS - 11
ER -