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

doi:10.1038/ng.3683

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 journal › Article › peer-review

190 Scopus citations

Abstract

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 language	English
Pages (from-to)	1500-1507
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	12
DOIs	https://doi.org/10.1038/ng.3683
State	Published - 1 Dec 2016
Externally published	Yes

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

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Hao, J. J., Lin, D. C., Dinh, H. Q., Mayakonda, A., Jiang, Y. Y., Chang, C., Jiang, Y., Lu, C. C., Shi, Z. Z., Xu, X., Zhang, Y., Cai, Y., Wang, J. W., Zhan, Q. M., Wei, W. Q., Berman, B. P., Wang, M. R., & Koeffler, H. P. (2016). Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma. Nature Genetics, 48(12), 1500-1507. https://doi.org/10.1038/ng.3683

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title = "Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma",

abstract = "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.",

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

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Hao, JJ, Lin, DC, Dinh, HQ, Mayakonda, A, Jiang, YY, Chang, C, Jiang, Y, Lu, CC, Shi, ZZ, Xu, X, Zhang, Y, Cai, Y, Wang, JW, Zhan, QM, Wei, WQ, Berman, BP, Wang, MR & Koeffler, HP 2016, 'Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma', Nature Genetics, vol. 48, no. 12, pp. 1500-1507. https://doi.org/10.1038/ng.3683

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T1 - Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma

AU - Hao, Jia Jie

AU - Lin, De Chen

AU - Dinh, Huy Q.

AU - Mayakonda, Anand

AU - Jiang, Yan Yi

AU - Chang, Chen

AU - Jiang, Ye

AU - Lu, Chen Chen

AU - Shi, Zhi Zhou

AU - Xu, Xin

AU - Zhang, Yu

AU - Cai, Yan

AU - Wang, Jin Wu

AU - Zhan, Qi Min

AU - Wei, Wen Qiang

AU - Berman, Benjamin P.

AU - Wang, Ming Rong

AU - Koeffler, H. Phillip

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N2 - 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.

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

Abstract

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