Journal Article

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

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

2016

Overview

Ming-Rong Wang, Benjamin Berman and colleagues perform whole-exome sequencing and global methylation profiling on different tumor regions of esophageal squamous cell carcinoma. They find evidence for intratumoral heterogeneity and identify late driver mutations targeting oncogenes and early driver mutations occurring in tumor-suppressor genes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/23 / 631/67/1504/1477 / 692/308/2056 / Agriculture / Animal Genetics and Genomics / Biomedicine / Cancer / Cancer Research / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - pathology / Clonal Evolution - genetics / Clone Cells - metabolism / Clone Cells - pathology / Cohort Studies / Deoxyribonucleic acid / DNA / DNA Methylation / Epigenetic inheritance / Epigenetics / Esophageal cancer / Esophageal Neoplasms - genetics / Esophageal Neoplasms - pathology / Esophagus / Evolution / Exome - genetics / Gene expression / Gene Expression Regulation, Neoplastic / Gene Function / Genomes / Heterogeneity / High-Throughput Nucleotide Sequencing / Human Genetics / Humans / Medical schools / Methylation / Mutation / Mutation - genetics / Neoplasm Proteins - genetics / Phylogenetics / Phylogeny / Science / Squamous cell carcinoma / Studies / Trees / Tumor proteins / Tumors