Theranostics 2020; 10(7):3035-3048. doi:10.7150/thno.42559 This issue Cite

Research Paper

Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma

Huajing Teng1,2,3#, Meiying Xue2,4#, Jialong Liang2, Xingxing Wang1, Lu Wang2, Wenqing Wei2,4, Chao Li1, Ze Zhang1, Qinglan Li2,4, Xia Ran2,4, Xiaohui Shi2,4, Wanshi Cai2, Weihu Wang3, Hengjun Gao5,6✉, Zhongsheng Sun1,2✉

1. Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China
2. Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China
4. University of Chinese Academy of Sciences, Beijing, China
5. Institute of Digestive Diseases, Tongji University School of Medicine, Shanghai, China
6. National Engineering Center for Biochip at Shanghai, Shanghai, China
#Authors contributed equally to this work.

Citation:
Teng H, Xue M, Liang J, Wang X, Wang L, Wei W, Li C, Zhang Z, Li Q, Ran X, Shi X, Cai W, Wang W, Gao H, Sun Z. Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics 2020; 10(7):3035-3048. doi:10.7150/thno.42559. https://www.thno.org/v10p3035.htm
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Abstract

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Background: Esophageal squamous cell carcinoma (ESCC), one of the leading causes of cancer mortality worldwide, is a heterogeneous cancer with diverse clinical manifestations. However, little is known about the epigenetic heterogeneity and its clinical relevance for this prevalent cancer.

Methods: We generated 7.56 Tb single-base resolution whole-genome bisulfite sequencing data for 84 ESCC and paired paraneoplastic tissues. The analysis identified inter- and intratumor DNA methylation (DNAm) heterogeneity, epigenome-wide DNAm alterations together with the functional regulators involved in the hyper- or hypomethylated regions, and their association with clinical features. We then validated the correlation between the methylation level of specific regions and clinical outcomes of 96 ESCC patients in an independent cohort.

Results: ESCC manifested substantial inter- and intratumor DNAm heterogeneity. The high intratumor DNAm heterogeneity was associated with lymph node metastasis and worse overall survival. Interestingly, hypermethylated regions in ESCC were enriched in promoters of numerous transcription factors, and demethylated noncoding regions related to RXR transcription factor binding appeared to contribute to the development of ESCC. Furthermore, we identified numerous DNAm alterations associated with carcinogenesis and lymph node metastasis of ESCC. We also validated three novel prognostic markers for ESCC, including one each in the promoter of CLK1, the 3' untranslated region of ZEB2, and the intergenic locus surrounded by several lncRNAs.

Conclusions: This study presents the first population-level resource for dissecting base-resolution DNAm variation in ESCC and provides novel insights into the ESCC pathogenesis and progression, which might facilitate diagnosis and prognosis for this prevalent malignancy.

Keywords: epigenetic heterogeneity, cancer mortality, whole-genome bisulfite sequencing, prognostic markers, personalized medicine


Citation styles

APA
Teng, H., Xue, M., Liang, J., Wang, X., Wang, L., Wei, W., Li, C., Zhang, Z., Li, Q., Ran, X., Shi, X., Cai, W., Wang, W., Gao, H., Sun, Z. (2020). Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics, 10(7), 3035-3048. https://doi.org/10.7150/thno.42559.

ACS
Teng, H.; Xue, M.; Liang, J.; Wang, X.; Wang, L.; Wei, W.; Li, C.; Zhang, Z.; Li, Q.; Ran, X.; Shi, X.; Cai, W.; Wang, W.; Gao, H.; Sun, Z. Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics 2020, 10 (7), 3035-3048. DOI: 10.7150/thno.42559.

NLM
Teng H, Xue M, Liang J, Wang X, Wang L, Wei W, Li C, Zhang Z, Li Q, Ran X, Shi X, Cai W, Wang W, Gao H, Sun Z. Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics 2020; 10(7):3035-3048. doi:10.7150/thno.42559. https://www.thno.org/v10p3035.htm

CSE
Teng H, Xue M, Liang J, Wang X, Wang L, Wei W, Li C, Zhang Z, Li Q, Ran X, Shi X, Cai W, Wang W, Gao H, Sun Z. 2020. Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics. 10(7):3035-3048.

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