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Original article
Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
  1. Ruiping Wang1,
  2. Shumei Song2,
  3. Kazuto Harada2,3,
  4. Fatemeh Ghazanfari Amlashi2,
  5. Brian Badgwell4,
  6. Melissa Pool Pizzi2,
  7. Yan Xu2,
  8. Wei Zhao2,
  9. Xiaochuan Dong2,
  10. Jiangkang Jin2,
  11. Ying Wang2,
  12. Ailing Scott2,
  13. Lang Ma2,
  14. Longfei Huo2,
  15. Diego Vicente4,
  16. Mariela Blum Murphy2,
  17. Namita Shanbhag2,
  18. Ghia Tatlonghari2,
  19. Irene Thomas2,
  20. Jane Rogers5,
  21. Makoto Kobayashi6,
  22. Jody Vykoukal6,
  23. Jeannelyn Santiano Estrella7,
  24. Sinchita Roy-Chowdhuri7,
  25. Guangchun Han1,
  26. Shaojun Zhang1,
  27. Xizeng Mao1,
  28. Xingzhi Song1,
  29. Jianhua Zhang1,
  30. Jian Gu8,
  31. Randy L Johnson9,
  32. George Adrian Calin10,
  33. Guang Peng6,
  34. Ju-Seog Lee11,
  35. Samir M Hanash6,
  36. Andrew Futreal1,
  37. Zhenning Wang12,
  38. Linghua Wang1,
  39. Jaffer A Ajani2
  1. 1 Genomic Medicine, UT MDACC, Houston, Texas, USA
  2. 2 GI Medical Oncology, UT MDACC, Houston, Texas, USA
  3. 3 Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
  4. 4 Surgical Oncology, UT MDACC, Houston, Texas, USA
  5. 5 Pharmacy Clinical Programs, UT MDACC, Houston, TX, USA
  6. 6 Clinical Cancer Prevention, UT MDACC, Houston, Texas, USA
  7. 7 Pathology, UT MDACC, Houston, Texas, USA
  8. 8 Epidemiology, UT MDACC, Houston, Texas, USA
  9. 9 Cancer Biology, UT MDACC, Houston, Texas, USA
  10. 10 Experimental Therapeutics, UT MDACC, Houston, Texas, USA
  11. 11 Systems Biology, UT MDACC, Houston, Texas, USA
  12. 12 Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, China
  1. Correspondence to Dr Shumei Song, Department of Gastrointestinal Medical Oncology, UT MD. Anderson Cancer Center, Houston, TX 77030, USA; ssong{at}mdanderson.org, Dr Linghua Wang, Department of Genomic Medicine, UTMD. Anderson Cancer Center, Houston, TX 77030, USA; lwang22{at}mdanderson.org and Dr Jaffer A Ajani, Department of Gastrointestinal Medical Oncology, UTMD. Anderson Cancer Center, Houston, TX 77030, USA; jajani{at}mdanderson.org

Abstract

Objective Peritoneal 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.

Design We 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.

Results We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, 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.

Conclusions We 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.

  • cancer genetics
  • gastric cancer
  • gastrointestinal cancer
  • gene expression
  • mutations

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • RW, SS and KH contributed equally.

  • Contributors SS, LW and JAA conceived and jointly supervised the study. RW conducted the major bioinformatics and biostatistics analysis of the multiplatform data, generated figures and tables for the manuscript. JZ, XS and XM contributed to raw WES data processing. GH and SZ assisted with WES and RNA-seq analysis. BB, MM, FGA, SC and JE assisted with clinical samples consent, collection and pathological evaluation. KH took charge of ascites cells isolations, DNA/RNA extraction and coordinated with DNA core facility for WES and RNA-seq and gathered all patients’ clinical information. YX, MP, JJ, YW, AS, LM, LH, NS, MK, JV, JG, PG, J-SL and ZW assisted and coordinated for tissues and ascites cells processing and other related analyses and experiments. LW, RW, SS, KH and JA wrote the manuscript. LW, JAA, RW, SS, KH, GZ, SH, ZW and AF revised the manuscript.

  • Funding This study was supported in part by the National Cancer Institute awards CA129906, CA127672, CA138671 and CA172741 and the DOD grants: CA150334 and CA162445 to JAA and DOD grants CA160433 and CA170906 to SS, and the start-up research funds provided to LW by the Department of Genomic Medicine, Division of Cancer Medicine of MD Anderson Cancer Center. This study was also supported by SMF Core grant CA016672 (SMF).

  • Competing interests None declared.

  • Ethics approval This project was approved by the institutional review committee.

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

  • Data sharing statement All WES and RNA-Seq data have been deposited at the European Genome-phenome Archive (EGA). The datasets can be fully accessed under the accession number EGAS00001003180. Further information about EGA can be found on https://ega-archive.org (’the EGA of human data consented for biomedical research': http://www.nature.com/ng/journal/v47/n7/full/ng.3312.html).

  • Author note Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to JA (jajani@mdanderson.org), SS (ssong@mdanderson.org) or LW (lwang22@mdanderson.org).

  • Patient consent for publication Not required.

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