title: Prospective comprehensive genomic profiling of advanced gastric carcinoma cases reveals frequent clinically relevant genomic alterations and new routes for targeted therapies.
abstract: BACKGROUND
  Gastric cancer (GC) is a major global cancer burden and the second most common cause of global cancer-related deaths. The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy improves survival for ERBB2-amplified advanced GC patients; however, the majority of GC patients do not harbor this alteration and thus cannot benefit from targeted therapy under current practice paradigms.
  
  
  METHODS
  Prospective comprehensive genomic profiling of 116 predominantly locally advanced or metastatic (90.0%) gastric cancer cases was performed to identify genomic alterations (GAs) associated with a potential response to targeted therapies approved by the U.S. Food and Drug Administration or targeted therapy-based clinical trials.
  
  
  RESULTS
  Overall, 78% of GC cases harbored one clinically relevant GA or more, with the most frequent alterations being found in TP53 (50%), ARID1A (24%), KRAS (16%), CDH1 (15%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.5%), PIK3CA (8.6%), MLL2 (6.9%), FGFR2 (6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations were detected in 20.6% of cases, primarily ERBB2, FGFR2, and MET amplification, with ERBB2 alterations evenly split between amplifications and base substitutions. Rare BRAF mutations (2.6%) were also observed. One MET-amplified GC patient responded for 5 months to crizotinib, a multitargeted ALK/ROS1/MET inhibitor.
  
  
  CONCLUSIONS
  Comprehensive genomic profiling of GC identifies clinically relevant GAs that suggest benefit from targeted therapy including MET-amplified GC and ERBB2 base substitutions.
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Siraj@Foundationmedicine.com.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sanford
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Rubinson
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Palma
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Catenacci
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Erlich
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA; Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014481:United States
chemical_list: D009363:Neoplasm Proteins
keywords: Gastric cancer; MET; Mutation; Profiling; Sequencing; Targeted therapy