title: Genomic and molecular characterization of esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
authors.affiliation: 1] Cedars-Sinai Medical Center, Division of Hematology/Oncology, University of California Los Angeles School of Medicine, Los Angeles, California, USA. [2] Cancer Science Institute of Singapore, National University of Singapore, Singapore. [3].
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: 1] State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. [2].
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Hao
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. [2].
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: 1] Cancer Science Institute of Singapore, National University of Singapore, Singapore. [2].
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Xuan
authors.initials: X
authors.lastname: Meng
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.identifier: 0000000331399272
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Varela
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ding
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Manoj
authors.initials: M
authors.lastname: Garg
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Zhi-Zhou
authors.initials: ZZ
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Wen-Yue
authors.initials: WY
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts, USA.
authors.forename: Ori
authors.initials: O
authors.lastname: Kalid
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
authors.affiliation: 1] Cedars-Sinai Medical Center, Division of Hematology/Oncology, University of California Los Angeles School of Medicine, Los Angeles, California, USA. [2] Cancer Science Institute of Singapore, National University of Singapore, Singapore. [3] National University Cancer Institute, National University Hospital Singapore, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D059472:Exome / Q000235:genetics*; D005822:Genetic Vectors; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D028884:Karyopherins / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein