CfDNA Hydroxymethylcytosine Profiling for Detection Metastasis and Recurrence of Esophageal Squamous Cell Carcinoma

Overview

Journal World J Surg Oncol

Publisher Biomed Central

Specialties General Surgery
Oncology

Date 2025 Mar 16

PMID 40089765

Authors

Subinuer Kuerban

Hangyu Chen

Long Chen

Lei Zhang

Xuehui Li

Baixin Zhen

Hong Xiao

Yingzhu Chen

Haitao Zhou

Zhen Liang

Guobing Xu

Yicun Tao

Jian Lin

Xiaozheng Kang

Affiliations

Soon will be listed here.

Abstract

Background: A blood-based approach to monitor metastasis and recurrence of esophageal squamous cell carcinoma (ESCC) remains undeveloped. This study aimed to establish a dependable model utilizing cfDNA 5-hydroxymethylcytosines (5hmC) signatures to detect these conditions in ESCC.

Methods: The 5hmC-Seal technique was employed to generate comprehensive 5hmC profiles from the plasma cell-free DNA (cfDNA) of 122 ESCC patients, classified into 72 with metastasis, 50 without metastasis, 30 with recurrence, and 92 without recurrence. Initial steps involved identifying distinct hydroxymethylation signatures linked to metastasis and recurrence. Machine learning algorithms were then utilized to construct predictive models.

Results: The study confirmed that 5hmC-based markers are predictive of metastasis and recurrence among ESCC patients. The analysis of 14 5hmC biomarkers revealed a sensitivity of 88.90% and a specificity of 84.00% (AUC = 0.922) in differentiating patients with ESCC metastasis from those without in the validation cohort. Similarly, 11 5hmC biomarkers showed a sensitivity of 93.30% and a specificity of 89.10% (AUC = 0.936) in identifying recurrent versus non-recurrent ESCC cases. Additionally, a wp-score for metastasis and recurrence, derived from the 5hmC marker, prognosticated patient outcomes.

Conclusions: The findings indicate that 5hmC markers from cfDNA serve as effective epigenetic indicators for the non-invasive detection of ESCC metastasis and recurrence.

References

Arnold M, Soerjomataram I, Ferlay J, Forman D . Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2014; 64(3):381-7. DOI: 10.1136/gutjnl-2014-308124. View

Hamai Y, Hihara J, Emi M, Furukawa T, Ibuki Y, Yamakita I . Treatment Outcomes and Prognostic Factors After Recurrence of Esophageal Squamous Cell carcinoma. World J Surg. 2017; 42(7):2190-2198. DOI: 10.1007/s00268-017-4430-8. View

Jiang L, Lin X, Chen F, Qin X, Yan Y, Ren L . Current research status of tumor cell biomarker detection. Microsyst Nanoeng. 2023; 9:123. PMC: 10556054. DOI: 10.1038/s41378-023-00581-5. View

Das S, Dey M, Devireddy R, Gartia M . Biomarkers in Cancer Detection, Diagnosis, and Prognosis. Sensors (Basel). 2024; 24(1). PMC: 10780704. DOI: 10.3390/s24010037. View

Bai J, Qiu S, Zhang G . Molecular and functional imaging in cancer-targeted therapy: current applications and future directions. Signal Transduct Target Ther. 2023; 8(1):89. PMC: 9971190. DOI: 10.1038/s41392-023-01366-y. View

Sekiguchi M, Matsuda T . Limited usefulness of serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels for gastrointestinal and whole-body cancer screening. Sci Rep. 2020; 10(1):18202. PMC: 7585432. DOI: 10.1038/s41598-020-75319-8. View

Yuan Z, Wang X, Geng X, Li Y, Mu J, Tan F . Liquid biopsy for esophageal cancer: Is detection of circulating cell-free DNA as a biomarker feasible?. Cancer Commun (Lond). 2020; 41(1):3-15. PMC: 7819547. DOI: 10.1002/cac2.12118. View

Labgaa I, Villanueva A, Dormond O, Demartines N, Melloul E . The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication. Cancers (Basel). 2021; 13(4). PMC: 7914891. DOI: 10.3390/cancers13040659. View

Osumi H, Shinozaki E, Yamaguchi K, Zembutsu H . Clinical utility of circulating tumor DNA for colorectal cancer. Cancer Sci. 2019; 110(4):1148-1155. PMC: 6447957. DOI: 10.1111/cas.13972. View

10.

Ito S, Shen L, Dai Q, Wu S, Collins L, Swenberg J . Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011; 333(6047):1300-3. PMC: 3495246. DOI: 10.1126/science.1210597. View

11.

Branco M, Ficz G, Reik W . Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet. 2011; 13(1):7-13. DOI: 10.1038/nrg3080. View

12.

Tahiliani M, Koh K, Shen Y, Pastor W, Bandukwala H, Brudno Y . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929):930-5. PMC: 2715015. DOI: 10.1126/science.1170116. View

13.

Laird P . The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003; 3(4):253-66. DOI: 10.1038/nrc1045. View

14.

Chen H, Zhang W, Zhang L, Yang P, Li F, Yang Z . 5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients. Clin Epigenetics. 2021; 13(1):33. PMC: 7879534. DOI: 10.1186/s13148-020-00973-8. View

15.

Wang Z, Du M, Yuan Q, Guo Y, Hutchinson J, Su L . Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers. Neoplasia. 2020; 22(3):154-161. PMC: 7021546. DOI: 10.1016/j.neo.2020.01.001. View

16.

Tong M, Gao S, Qi W, Shi C, Qiu M, Yang F . 5-Hydroxymethylcytosine as a potential epigenetic biomarker in papillary thyroid carcinoma. Oncol Lett. 2019; 18(3):2304-2309. PMC: 6676597. DOI: 10.3892/ol.2019.10531. View

17.

Thomson J, Meehan R . The application of genome-wide 5-hydroxymethylcytosine studies in cancer research. Epigenomics. 2016; 9(1):77-91. DOI: 10.2217/epi-2016-0122. View

18.

Zhang F, Liu Y, Zhang Z, Li J, Wan Y, Zhang L . 5-hydroxymethylcytosine loss is associated with poor prognosis for patients with WHO grade II diffuse astrocytomas. Sci Rep. 2016; 6:20882. PMC: 4749994. DOI: 10.1038/srep20882. View

19.

Chen K, Zhang J, Guo Z, Ma Q, Xu Z, Zhou Y . Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer. Cell Res. 2015; 26(1):103-18. PMC: 4816137. DOI: 10.1038/cr.2015.150. View

20.

Mariani C, Madzo J, Moen E, Yesilkanal A, Godley L . Alterations of 5-hydroxymethylcytosine in human cancers. Cancers (Basel). 2013; 5(3):786-814. PMC: 3795365. DOI: 10.3390/cancers5030786. View