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Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma.


ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC4385186 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma.

Zhang Ling L   Zhou Yong Y   Cheng Caixia C   Cui Heyang H   Cheng Le L   Kong Pengzhou P   Wang Jiaqian J   Li Yin Y   Chen Wenliang W   Song Bin B   Wang Fang F   Jia Zhiwu Z   Li Lin L   Li Yaoping Y   Yang Bin B   Liu Jing J   Shi Ruyi R   Bi Yanghui Y   Zhang Yanyan Y   Wang Juan J   Zhao Zhenxiang Z   Hu Xiaoling X   Yang Jie J   Li Hongyi H   Gao Zhibo Z   Chen Gang G   Huang Xuanlin X   Yang Xukui X   Wan Shengqing S   Chen Chao C   Li Bin B   Tan Yongkai Y   Chen Longyun L   He Minghui M   Xie Sha S   Li Xiangchun X   Zhuang Xuehan X   Wang Mengyao M   Xia Zhi Z   Luo Longhai L   Ma Jie J   Dong Bing B   Zhao Jiuzhou J   Song Yongmei Y   Ou Yunwei Y   Li Enming E   Xu Liyan L   Wang Jinfen J   Xi Yanfeng Y   Li Guodong G   Xu Enwei E   Liang Jianfang J   Yang Xiaofeng X   Guo Jiansheng J   Chen Xing X   Zhang Yanbo Y   Li Qingshan Q   Liu Lixin L   Li Yingrui Y   Zhang Xiuqing X   Yang Huanming H   Lin Dongxin D   Cheng Xiaolong X   Guo Yongjun Y   Wang Jun J   Zhan Qimin Q   Cui Yongping Y  

American journal of human genetics 20150401 4


Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APO  ...[more]

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