Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma

Jia Jie Hao, De Chen Lin, Huy Q. Dinh, Anand Mayakonda, Yan Yi Jiang, Chen Chang, Ye Jiang, Chen Chen Lu, Zhi Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin Wu Wang, Qi Min Zhan, Wen Qiang Wei, Benjamin P. Berman, Ming Rong Wang*, H. Phillip Koeffler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

177 Scopus citations


Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC.

Original languageAmerican English
Pages (from-to)1500-1507
Number of pages8
JournalNature Genetics
Issue number12
StatePublished - 1 Dec 2016
Externally publishedYes

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© 2016 Nature America, Inc. part of Springer Nature, All Rights reserved.


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