Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis

Arnaldo N. S. Silva, Jordy Coffa, Varsha Menon, Lindsay C. Hewitt, Kakoli Das, Yohei Miyagi, Dan Bottomley, Hayley Slaney, Toru Aoyama, Wolfram Mueller, Tomio Arai, Iain B. Tan, Niantao Deng, Xiu B. Chan, Patrick Tan, Akira Tsuburaya, Kentaro Sakamaki, Jeremy D. Hayden, Takaki Yoshikawa, Ilse ZondervanSuvi Savola, Heike I. Grabsch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

Abstract

Objective:To establish the gene copy number status of receptor tyrosine kinase (RTK) and downstream signaling (DSS) genes genes in primary gastric cancer (primGC) and matched lymph node metastases (LNmet).Background:Evidence suggests that coamplification between RTKs and DSSs and conversion between primGC and LNmet are associated with resistance to targeted therapy.Methods:DNA from 237 Japanese primGC and 103 matched LNmet was analyzed using a newly developed multiplex ligation-dependent probe amplification (MLPA) probemix to investigate RTK (EGFR, HER2, FGFR2, and MET) and DSS (PIK3CA, KRAS, MYC, and CCNE1) gene copy number status. Results were compared between primGC and LNmet and related to clinicopathological data including survival.Results:A total of 150 (63%) primGC had either RTK or DSS amplification. DSS coamplification was more frequent than RTK coamplification in primGC and LNmets. Moreover, 70 (30%) GC showed a disconcordant RTK and/or DSS gene copy number status between primGC and LNmet, most common was negative conversion for DSS genes (n=40 GC). The presence of RTK amplification in primGC was related to poorer survival in univariate analysis (P=0.04).Conclusions:This is the first and most comprehensive study in gastric cancer investigating the concordance between gene copy number status of targetable RTKs and downstream signaling oncogenes in primGC and LNmets. Future studies need to establish whether the relative high frequency of RTK and DSS coamplification and/or the relative high rate of negative conversion in LNmet can potentially explain recent failures of RTK targeted therapy in gastric cancer patients.
Original languageEnglish
Pages (from-to)114-121
Number of pages8
JournalAnnals of Surgery
Volume267
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • gastric cancer
  • gastric cancer heterogeneity
  • gene copy number status
  • lymph node metastasis
  • receptor tyrosine kinases
  • resistance mechanisms
  • DEPENDENT PROBE AMPLIFICATION
  • IN-SITU HYBRIDIZATION
  • LABEL PHASE-3 TRIAL
  • CLINICOPATHOLOGICAL SIGNIFICANCE
  • ACQUIRED-RESISTANCE
  • TARGETED THERAPIES
  • PROTEIN EXPRESSION
  • COLORECTAL-CANCER
  • CARCINOMA
  • HER2

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