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Nat Genet. 2014 Oct;46(10):1097-102. doi: 10.1038/ng.3076. Epub 2014 Aug 24.

Genetic landscape of esophageal squamous cell carcinoma.

Author information

  • 1Department of Thoracic Surgery, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, China.
  • 2Department of Clinical Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 3Department of Pathology, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, China.
  • 4Department of Thoracic Surgery, Peking University Cancer Hospital, Beijing, China.
  • 5Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

PMID:
25151357
DOI:
10.1038/ng.3076
[PubMed - indexed for MEDLINE]
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