Shinji Kohsaka1, Takuo Hayashi2, Masaaki Nagano3, Toshihide Ueno4, Shinya Kojima4, Masahito Kawazu4, Yuichi Shiraishi4, Satsuki Kishikawa2, Yoshiyuki Suehara5, Fumiyuki Takahashi6, Kazuhisa Takahashi6, Kenji Suzuki7, Kazuya Takamochi7, Hiroyuki Mano4. 1. Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan. Electronic address: skohsaka@ncc.go.jp. 2. Department of Human Pathology, Juntendo University, Graduate School of Medicine, Tokyo, Japan. 3. Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan; Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. 4. Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan. 5. Department of Orthopedic Surgery, Juntendo University, Graduate School of Medicine, Tokyo, Japan. 6. Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan. 7. Department of General Thoracic Surgery, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
Abstract
INTRODUCTION: Studies are yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. METHODS: We analyzed 996 cases of Japanese LUAD and performed whole-exome sequencing and RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathologic characteristics among the 996 cases. RESULTS: Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas study. Two actionable novel fusions of FGFR2 and NRG2α were also identified. Clustering on the basis of mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using The Cancer Genome Atlas cohort. Among the 996 cases, each driver alteration is distributed across all histologic subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. CONCLUSIONS: This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.
INTRODUCTION: Studies are yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. METHODS: We analyzed 996 cases of Japanese LUAD and performed whole-exome sequencing and RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathologic characteristics among the 996 cases. RESULTS: Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas study. Two actionable novel fusions of FGFR2 and NRG2α were also identified. Clustering on the basis of mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using The Cancer Genome Atlas cohort. Among the 996 cases, each driver alteration is distributed across all histologic subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. CONCLUSIONS: This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.
Authors: Maurício Fernando Silva Almeida Ribeiro; Luiza Lara Gadotti; Karina Perez Sacardo; Carlos Diego Holanda Lopes; Rodrigo Saddi; João Victor Machado Alessi; Mariana Petaccia de Macedo; Ellen Caroline Toledo do Nascimento; Leonardo de Abreu Testagrossa; Artur Katz Journal: SAGE Open Med Case Rep Date: 2022-05-21
Authors: Alexander Drilon; Natasha Rekhtman; Jason C Chang; Michael Offin; Christina Falcon; David Brown; Brian R Houck-Loomis; Fanli Meng; Vasilisa A Rudneva; Helen H Won; Sharon Amir; Joseph Montecalvo; Patrice Desmeules; Kyuichi Kadota; Prasad S Adusumilli; Valerie W Rusch; Sarah Teed; Joshua K Sabari; Ryma Benayed; Khedoudja Nafa; Laetitia Borsu; Bob T Li; Alison M Schram; Maria E Arcila; William D Travis; Marc Ladanyi Journal: Clin Cancer Res Date: 2021-05-04 Impact factor: 12.531
Authors: Sai-Hong Ignatius Ou; Joanne Xiu; Misako Nagasaka; Bing Xia; Shannon S Zhang; Qing Zhang; Jeffrey J Swensen; David Spetzler; Wolfgang Michael Korn; Viola W Zhu; Stephen V Liu Journal: JTO Clin Res Rep Date: 2020-12-24
Authors: Alexander Drilon; Michael Duruisseaux; Ji-Youn Han; Masaoki Ito; Christina Falcon; Soo-Ryum Yang; Yonina R Murciano-Goroff; Haiquan Chen; Morihito Okada; Miguel Angel Molina; Marie Wislez; Philippe Brun; Clarisse Dupont; Eva Branden; Giulio Rossi; Alexa Schrock; Siraj Ali; Valérie Gounant; Fanny Magne; Torsten Gerriet Blum; Alison M Schram; Isabelle Monnet; Jin-Yuan Shih; Joshua Sabari; Maurice Pérol; Viola W Zhu; Misako Nagasaka; Robert Doebele; D Ross Camidge; Maria Arcila; Sai-Hong Ignatius Ou; Denis Moro-Sibilot; Rafael Rosell; Lucia Anna Muscarella; Stephen V Liu; Jacques Cadranel Journal: J Clin Oncol Date: 2021-06-02 Impact factor: 50.717
Authors: J Laskin; S V Liu; K Tolba; C Heining; R F Schlenk; P Cheema; J Cadranel; M R Jones; A Drilon; A Cseh; S Gyorffy; F Solca; M Duruisseaux Journal: Ann Oncol Date: 2020-09-09 Impact factor: 51.769