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Nat Genet. 2014 May;46(5):467-73. doi: 10.1038/ng.2935. Epub 2014 Mar 30.

Genomic and molecular characterization of esophageal squamous cell carcinoma.

Author information

1
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].
2
1] State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. [2].
3
1] Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. [2].
4
1] Cancer Science Institute of Singapore, National University of Singapore, Singapore. [2].
5
State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
6
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
7
Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
8
Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
9
Karyopharm Therapeutics, Natick, Massachusetts, USA.
10
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.

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.

PMID:
24686850
PMCID:
PMC4070589
DOI:
10.1038/ng.2935
[Indexed for MEDLINE]
Free PMC Article
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