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<p>5-hydroxymethylcytosine (5hmC) is a stable epigenomic mark associated with gene regulation and tumorigenesis. To evaluate its potential for multi-cancer detection, epigenomic distribution of 5hmC was analyzed in tumor tissues (<i>n</i> = 217), normal tissues (<i>n</i> = 50), and cell-free DNA (cfDNA) from cancer (<i>n</i> = 1009) and non-cancer subjects (<i>n</i> = 1678) across breast, colon, lung, ovarian, and pancreatic cancers. Differential analysis revealed extensive redistribution of 5hmC in early-stage tumors that persisted into the late-stage, while global 5hmC abundance decreased in all tumors. Two distinct patterns of hydroxymethylation distribution were identified: one common across cancers and another tissue specific. Differential hydroxymethylation regions (DhmRs) that were tumor tissue specific had significantly improved cancer prediction in cfDNA. A multinomial logistic regression model was trained on tissue-specific DhmRs to predict Tissue of Tumor Origin (TOTO) of cfDNA with 85.2% accuracy. These findings demonstrate that stable, cancer-specific 5hmC signatures appear to be established early in tumorigenesis persist throughout disease progression, suggesting 5hmC as a potential pan-cancer marker for early and late-stage tumor detection via liquid biopsy.</p>

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5-hydroxymethylcytosine analysis reveals stable epigenomic changes in tumor tissue that enable cancer detection in cell-free DNA

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Yuan Xue,
  • Yuhong Ning,
  • Verena Friedl,
  • David Haan,
  • Anna Bergamaschi,
  • Gulfem D. Guler,
  • Kyle Hazen,
  • Aaron Scott,
  • Tierney Phillips,
  • Erin McCarthy,
  • Christopher K. Ellison,
  • Roger Malta,
  • Albert Nguyen,
  • Vanessa Lopez,
  • Romola Cavet,
  • Melissa Peters,
  • Judith Sheard,
  • William Gibb,
  • Shimul Chowdhury,
  • Wayne Volkmuth,
  • Samuel Levy

摘要

5-hydroxymethylcytosine (5hmC) is a stable epigenomic mark associated with gene regulation and tumorigenesis. To evaluate its potential for multi-cancer detection, epigenomic distribution of 5hmC was analyzed in tumor tissues (n = 217), normal tissues (n = 50), and cell-free DNA (cfDNA) from cancer (n = 1009) and non-cancer subjects (n = 1678) across breast, colon, lung, ovarian, and pancreatic cancers. Differential analysis revealed extensive redistribution of 5hmC in early-stage tumors that persisted into the late-stage, while global 5hmC abundance decreased in all tumors. Two distinct patterns of hydroxymethylation distribution were identified: one common across cancers and another tissue specific. Differential hydroxymethylation regions (DhmRs) that were tumor tissue specific had significantly improved cancer prediction in cfDNA. A multinomial logistic regression model was trained on tissue-specific DhmRs to predict Tissue of Tumor Origin (TOTO) of cfDNA with 85.2% accuracy. These findings demonstrate that stable, cancer-specific 5hmC signatures appear to be established early in tumorigenesis persist throughout disease progression, suggesting 5hmC as a potential pan-cancer marker for early and late-stage tumor detection via liquid biopsy.