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Am J Hum Genet. 2015 Apr 2;96(4):597-611. doi: 10.1016/j.ajhg.2015.02.017.

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

Author information

1
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
2
BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
3
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Pathology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
4
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
5
BGI-Yunnan, Kunming, Yunnan 650000, China.
6
Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, Henan 450008, China.
7
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
8
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of General Surgery, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
9
Department of Molecular Pathology, Henan Cancer Hospital, Zhengzhou, Henan 450008, China.
10
State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
11
Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China.
12
Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
13
Department of Pathology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
14
Department of Urology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
15
Department of General Surgery, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
16
Department of Endoscopy, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, China.
17
Department of Statistics, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
18
School of Pharmaceutical Sciences, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
19
Experimental Center of Science and Research, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
20
State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: zhanqimin@pumc.edu.cn.
21
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China. Electronic address: cuiy0922@yahoo.com.

Erratum in

  • Am J Hum Genet. 2015 Nov 5;97(5):769.

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.

PMID:
25839328
PMCID:
PMC4385186
DOI:
10.1016/j.ajhg.2015.02.017
[Indexed for MEDLINE]
Free PMC Article

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