title: Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung.
abstract: OBJECTIVE
  Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.
  
  
  METHODS
  We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).
  
  
  RESULTS
  We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).
  
  
  CONCLUSIONS
  LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757-65. ©2016 AACR.
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.|Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.|Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors: Tomohiro
authors: T
authors: Miyoshi
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan. sumemura@east.ncc.go.jp.|Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Shigeki
authors: S
authors: Umemura
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Yuki
authors: Y
authors: Matsumura
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors: Sachiyo
authors: S
authors: Mimaki
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors: Satoshi
authors: S
authors: Tada
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors: Hideki
authors: H
authors: Makinoshima
authors: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors: Genichiro
authors: G
authors: Ishii
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.|Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Hibiki
authors: H
authors: Udagawa
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.|Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Shingo
authors: S
authors: Matsumoto
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Kiyotaka
authors: K
authors: Yoh
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Seiji
authors: S
authors: Niho
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Hironobu
authors: H
authors: Ohmatsu
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Keiju
authors: K
authors: Aokage
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Tomoyuki
authors: T
authors: Hishida
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Junji
authors: J
authors: Yoshida
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Kanji
authors: K
authors: Nagai
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Koichi
authors: K
authors: Goto
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: Masahiro
authors: M
authors: Tsuboi
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors: Katsuya
authors: K
authors: Tsuchihara
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D018287:Carcinoma, Large Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000601:surgery; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology / Q000601:surgery; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D009363:Neoplasm Proteins