Identification of genomic alterations in oesophageal squamous cell cancer

被引：935

作者：

Song, Yongmei ^{[1
,2
]}

Li, Lin ^{[3
]}

Ou, Yunwei ^{[1
,2
,4
]}

Gao, Zhibo ^{[3
]}

Li, Enmin ^{[5
]}

Li, Xiangchun ^{[3
]}

Zhang, Weimin ^{[1
,2
]}

Wang, Jiaqian ^{[3
]}

Xu, Liyan ^{[6
]}

Zhou, Yong ^{[3
]}

Ma, Xiaojuan ^{[1
,2
]}

Liu, Lingyan ^{[1
,2
]}

Zhao, Zitong ^{[1
,2
]}

Huang, Xuanlin ^{[3
]}

Fan, Jing ^{[1
,2
]}

Dong, Lijia ^{[1
,2
]}

Chen, Gang ^{[3
]}

Ma, Liying ^{[1
,2
]}

Yang, Jie ^{[3
]}

Chen, Longyun ^{[3
]}

He, Minghui ^{[3
]}

Li, Miao ^{[3
]}

Zhuang, Xuehan ^{[3
]}

Huang, Kai ^{[3
]}

Qiu, Kunlong ^{[3
]}

Yin, Guangliang ^{[3
]}

Guo, Guangwu ^{[3
]}

Feng, Qiang ^{[3
]}

Chen, Peishan ^{[3
]}

Wu, Zhiyong ^{[7
]}

Wu, Jianyi ^{[5
]}

Ma, Ling ^{[1
,2
]}

Zhao, Jinyang ^{[3
]}

Luo, Longhai ^{[3
]}

Fu, Ming ^{[1
,2
]}

Xu, Bainan ^{[4
]}

Chen, Bo ^{[6
]}

Li, Yingrui ^{[3
]}

Tong, Tong ^{[1
,2
]}

Wang, Mingrong ^{[1
,2
]}

Liu, Zhihua ^{[1
,2
]}

Lin, Dongxin ^{[1
,2
]}

Zhang, Xiuqing ^{[3
]}

Yang, Huanming ^{[3
]}

Wang, Jun ^{[3
]}

Zhan, Qimin ^{[1
,2
]}

机构：

[1] Chinese Acad Med Sci, State Key Lab Mol Oncol, Canc Inst & Canc Hosp, Beijing 100021, Peoples R China

[2] Peking Union Med Coll, Beijing 100021, Peoples R China

[3] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Dept Neurosurg, Beijing 100853, Peoples R China

[5] Shantou Univ, Coll Med, Dept Biochem & Mol Biol, Key Lab Mol Biol High Canc Incidence Coastal Chao, Shantou 515041, Guangdong, Peoples R China

[6] Shantou Univ, Coll Med, Inst Oncol Pathol, Shantou 515041, Guangdong, Peoples R China

[7] Sun Yat Sen Univ, Affiliated Shantou Hosp, Shantou Cent Hosp, Dept Tumor Surg, Shantou 515041, Guangdong, Peoples R China

来源：

NATURE | 2014年 / 509卷 / 7498期

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

CIRCULAR BINARY SEGMENTATION; SOMATIC MUTATION; ADENOCARCINOMA; IMMORTALIZATION; ABERRATIONS; PATTERNS; EXOME;

D O I：

10.1038/nature13176

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide(1). Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%)(2,3). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

引用

页码：91 / +

页数：17

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