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Original research
Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma
  1. Dapeng Hao1,
  2. Siyuan He2,
  3. Kazuto Harada3,
  4. Melissa Pool Pizzi4,
  5. Yang Lu5,
  6. Pujun Guan1,
  7. Lu Chen1,
  8. Ruiping Wang1,
  9. Shaojun Zhang1,
  10. Matheus Sewastjanow-Silva4,
  11. Ahmed Abdelhakeem4,
  12. Namita Shanbhag4,
  13. Manoop Bhutani6,
  14. Guangchun Han1,
  15. Jeffrey H Lee6,
  16. Shuangtao Zhao1,
  17. Brian Weston6,
  18. Mariela Blum Murphy4,
  19. Rebecca Waters7,
  20. Jeannelyn Santiano Estrella7,
  21. Sinchita Roy-Chowdhuri7,
  22. Qiong Gan7,
  23. Ju-Seog Lee8,
  24. Guang Peng9,
  25. Samir M Hanash10,
  26. George Adrian Calin10,
  27. Xingzhi Song11,
  28. Jianhua Zhang11,
  29. Shumei Song4,
  30. Linghua Wang1,
  31. Jaffer A Ajani4
  1. 1 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  3. 3 Gastroenterological Surgery, Kumamoto University, Kumamoto, Kumamoto, Japan
  4. 4 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5 Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6 Gastroenterology Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  7. 7 Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  8. 8 Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  9. 9 Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  10. 10 Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  11. 11 Computational Genomics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Jaffer A Ajani, Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; jajani{at}mdanderson.org; Dr Linghua Wang, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; LWang22{at}mdanderson.org

Abstract

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

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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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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Footnotes

  • Twitter @A_Adel90

  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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