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.
- oesophageal cancer
- gastric adenocarcinoma
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Contributors LW and JAA conceived and jointly supervised the study. DH conducted the major bioinformatics and biostatistics analysis of the multiplatform data, generated figures and tables for the manuscript. SH, PG, R Wang, S Zhang, GH and S Zhao assisted with WES and RNA-seq analysis. JZ and XS contributed to raw WES data processing. KH, MP, YL, PG, LC, MS, AA, NS, MB, JL, BW, MM, R Waters, JE, SR, QG, JL, GP, SH, GC and SS assisted with clinical samples consent, collection and pathological evaluation and other related analyses and experiments. KH, MP, NS and SS took charge of DNA/RNA extraction and coordinated with core facility for WES and RNA-seq and gathered all patients’ clinical information. DH, SS, LW and JAA wrote the manuscript. LW, JAA and SS revised the manuscript.
Funding This research was supported by generous grants from the Caporella, Hyland, Sultan, Smith, Myers, Kevin, and Park families, as well as from the Stupid Strong Gastric Cancer Fund, V foundation, John Armstrong Fund, Golfers Against Cancer, Zeus Immunology Research Fund, Anonymous Donor, and two The University of Texas MD Anderson Cancer Center (Houston, Texas, USA) multidisciplinary grant programs. This research was also supported in part by the start-up research fund provided to LW by UT. MD Anderson Cancer Center (MDACC), National Cancer Institute grants (CA129906, CA127672, CA138671, and CA172741 (R01), CA241600-01 (R01)) and by Department of Defense grants (CA150334 and CA160445 (JAA); CA160433 and CA170906 (SS)) and by a grant from the Japan Society for the Promotion of Science Overseas Research Fellowships grant from the Japan Society for the Promotion of Science Overseas Research Fellowships (KH).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information. All sequencing data generated during this study have been deposited in the European Genome-phenome Archive (EGA). The data can be found under the accession number EGAS00001004887.
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