title: Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis.
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.
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors: Arnaldo N S
authors: ANS
authors: Silva
authors: MRC-Holland B.V, Research and Development Department, Amsterdam, The Netherlands.
authors: Jordy
authors: J
authors: Coffa
authors: Drug Design and Discovery Group, Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates.
authors: Varsha
authors: V
authors: Menon
authors: Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Lindsay C
authors: LC
authors: Hewitt
authors: Duke-NUS Medical School, Singapore.
authors: Kakoli
authors: K
authors: Das
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
authors: Yohei
authors: Y
authors: Miyagi
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors: Dan
authors: D
authors: Bottomley
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors: Hayley
authors: H
authors: Slaney
authors: Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
authors: Toru
authors: T
authors: Aoyama
authors: Gemeinschaftspraxis Pathologie, Starnberg, Germany.
authors: Wolfram
authors: W
authors: Mueller
authors: Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors: Tomio
authors: T
authors: Arai
authors: Division of Medical Oncology, National Cancer Centre, Singapore.
authors: Iain B
authors: IB
authors: Tan
authors: Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
authors: Niantao
authors: N
authors: Deng
authors: Genome Institute of Singapore, Singapore.
authors: Xiu B
authors: XB
authors: Chan
authors: Duke-NUS Medical School, Singapore.
authors: Patrick
authors: P
authors: Tan
authors: Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
authors: Akira
authors: A
authors: Tsuburaya
authors: Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan.
authors: Kentaro
authors: K
authors: Sakamaki
authors: Department of Upper Gastrointestinal Surgery, Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
authors: Jeremy D
authors: JD
authors: Hayden
authors: Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
authors: Takaki
authors: T
authors: Yoshikawa
authors: MRC-Holland B.V, Research and Development Department, Amsterdam, The Netherlands.
authors: Ilse
authors: I
authors: Zondervan
authors: MRC-Holland B.V, Research and Development Department, Amsterdam, The Netherlands.
authors: Suvi
authors: S
authors: Savola
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.|Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Heike I
authors: HI
authors: Grabsch
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D009367:Neoplasm Staging; D021141:Nucleic Acid Amplification Techniques; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000556:secondary; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; D020794:Receptor Protein-Tyrosine Kinases