title: Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm.
abstract: Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Cheol Keun
authors.initials: CK
authors.lastname: Park
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Park
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyo Song
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Hyung
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cheong
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Noh
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Kil
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
authors.affiliation: YUMS-KRIBB Medical Convergence Research Institute, Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Huh
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000465:Algorithms; D004268:DNA-Binding Proteins / Q000032:analysis; D055088:Early Detection of Cancer / Q000379:methods* / Q000592:standards; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization / Q000379:methods; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000032:analysis; D000070957:MutL Protein Homolog 1 / Q000032:analysis; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009154:Mutation; D009367:Neoplasm Staging; D017410:Practice Guidelines as Topic; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012367:RNA, Viral / Q000302:isolation & purification; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D019859:Proto-Oncogene Proteins c-met; D012367:RNA, Viral; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C495901:TP53 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human
keywords: amplification; gastric cancer; receptor tyrosine kinase; screening algorithm