Identification of genomic alterations in oesophageal squamous cell cancer

• Published in: Nature (London) Vol. 509; no. 7498; pp. 91 - 95
• Main Authors: Song, Yongmei, Li, Lin, Ou, Yunwei, Gao, Zhibo, Li, Enmin, Li, Xiangchun, Zhang, Weimin, Wang, Jiaqian, Xu, Liyan, Zhou, Yong, Ma, Xiaojuan, Liu, Lingyan, Zhao, Zitong, Huang, Xuanlin, Fan, Jing, Dong, Lijia, Chen, Gang, Ma, Liying, Yang, Jie, Chen, Longyun, He, Minghui, Li, Miao, Zhuang, Xuehan, Huang, Kai, Qiu, Kunlong, Yin, Guangliang, Guo, Guangwu, Feng, Qiang, Chen, Peishan, Wu, Zhiyong, Wu, Jianyi, Ma, Ling, Zhao, Jinyang, Luo, Longhai, Fu, Ming, Xu, Bainan, Chen, Bo, Li, Yingrui, Tong, Tong, Wang, Mingrong, Liu, Zhihua, Lin, Dongxin, Zhang, Xiuqing, Yang, Huanming, Wang, Jun, Zhan, Qimin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2014; Nature Publishing Group
• Subjects: 45/23; 631/67/69; Alcohol Drinking - adverse effects; Analysis; Biomarkers, Tumor - genetics; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Cycle - genetics; Chromosomes, Human, Pair 11 - genetics; Comparative Genomic Hybridization; DNA Copy Number Variations - genetics; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Esophagus; Exome - genetics; Female; Gene mutations; Genetic aspects; Genome, Human - genetics; Genomes; Genomics; Health aspects; Histones - metabolism; Humanities and Social Sciences; Humans; Identification and classification; letter; Male; MicroRNAs - genetics; multidisciplinary; Mutation; Mutation - genetics; Oncogenes - genetics; Oncology, Experimental; Phenotype; Receptors, Notch - genetics; Research projects; Risk Factors; Science; Spectrum analysis; Squamous cell carcinoma; Survival; Throat cancer; Tumor markers; Tumor proteins; Wnt Signaling Pathway - genetics
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13176

Using whole-genome and whole-exome sequencing, this study identifies eight significantly mutated genes in oesophageal squamous cell cancer, including two genes, ADAM29 and FAM135B , not previously associated with this cancer type. The genomic landscape of oesophageal cancer This paper reports the genomic analysis of samples from more than a hundred cases of oesophageal squamous cell carcinoma. Eight significantly mutated genes were identified, six of them well known as tumour-associated genes and two — ADAM29 and FAM135B — not previously described in this type of cancer. Analyses reveal frequent mutations in several important histone regulator genes and identify a microRNA encoded in the amplified 11q13.3-13.4 region as a novel oncogene. Furthermore, genetically, oesophageal cancer is shown to share common pathogenic mechanisms with head and neck squamous cell carcinoma. 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.