Development of mesenchymal subtype gene signature for clinical application in gastric cancer
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Jeeyun Lee1,*, Razvan Cristescu2,*, Kyoung-Mee Kim3,*, Kyung Kim1, Seung Tae Kim1, Se Hoon Park1 and Won Ki Kang1
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Genetics and Pharmacogenomics (GpGx), Merck Research Laboratories, Merck Sharpe & Dohme, Boston, MA, USA
3Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
*These authors have contributed equally to this work
Se Hoon Park, email: [email protected]
Keywords: stomach neoplasm, genomics, gene signature, subtypes, mesenchymal
Received: March 07, 2017 Accepted: July 18, 2017 Published: August 07, 2017
Previously, in the Asian Cancer Research Group (ACRG) project, we defined four distinct molecular subtypes in gastric cancer (GC). Mesenchymal (microsatellite stable with epithelial-to-mesenchymal transition phenotype, MSS/EMT) tumors showed the worst prognosis among all the subtypes. To develop a gene signature for predicting mesenchymal subtype GC, we conducted gene expression profiling using a NanoString assay in 70 ACRG specimens. The gene signature was validated in an independent set obtained from the prospective Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. The association between the mesenchymal subtype and survival was investigated. After cross-platform concordance test performed in 70 ACRG specimens, a 71-gene MSS/EMT signature was obtained. In the validation set, the gene signature predicted that 20 of 73 (27%) patients had mesenchymal tumors. Patients with mesenchymal subtype had diffuse GC, poorly-differentiated or signet ring cell carcinoma, and were microsatellite stable. The estimated hazard ratio for survival in patients with mesenchymal GC compared to those with non-mesenchymal tumors was 2.262 (95% confidence interval, 1.410 to 3.636; P=0.001). The survival difference remained significant when the subtypes were analyzed according to clinical prognostic parameters. This study suggested that the NanoString-based 71-gene signature for mesenchymal subtype is a strong predictor of the outcome in patients with GC.
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