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<p>Glioblastoma is the most common and deadly brain cancer in adults. Although the disease disrupts the blood-brain barrier and exposes the tumor to the systemic circulation, using circulating cell-free DNA as a non-invasive biomarker for diagnosing glioblastoma remains elusive. The main obstacles are the confounding effects from artifactual variants in cell-free DNA caused by errors during next-generation sequencing and real variants in cell-free DNA originating from white blood cells that acquired somatic mutations during normal aging. Here, we developed and validated TrueR sequencing to overcome next-generation sequencing-related false positives in cell-free DNA. Subsequently, TrueR identified molecular features unique to tumor-derived cell-free DNA (i.e., circulating tumor DNA) that are detectable in blood during a tumor-naïve search. Specifically, variants associated with glioblastoma circulating tumor DNA were exclusively present in cell-free DNA (i.e., absent in white blood cell DNA) and showed gene-specific subclones. These features were uncommon in low-grade glioma, stroke, and age-related somatic mosaicism of white blood cells. We also detail a variant-agnostic method, demonstrating that copy number gains and losses in short cell-free DNA fragments (&lt;90 bp) support the detection of glioblastoma. Finally, we present evidence that our findings extend beyond glioblastoma, supporting the broader advancement of the liquid biopsy.</p>

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Molecular features unique to circulating tumor DNA enable the tumor-naïve liquid biopsy of glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

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  • Hunter R. Underhill,
  • Drew L. Sellers,
  • Sabine Hellwig,
  • Hediyeh Baradaran,
  • Mary P. Bronner,
  • Alun Thomas,
  • Sarah Menacho,
  • Christian J. Davidson,
  • Rachna Malani,
  • Andrew Farrell,
  • Michael Karsy,
  • David A. Nix,
  • Yingqi Zhang,
  • Laura A. Boatz,
  • Joe Mendez,
  • Lindsay Burt,
  • Donald Cannon,
  • Charlie S. Dean,
  • Brion E. Harrison,
  • Samuel Stevenson,
  • Kinga Aitken,
  • Stefan M. Pulst,
  • Howard Colman,
  • Randy L. Jensen

摘要

Glioblastoma is the most common and deadly brain cancer in adults. Although the disease disrupts the blood-brain barrier and exposes the tumor to the systemic circulation, using circulating cell-free DNA as a non-invasive biomarker for diagnosing glioblastoma remains elusive. The main obstacles are the confounding effects from artifactual variants in cell-free DNA caused by errors during next-generation sequencing and real variants in cell-free DNA originating from white blood cells that acquired somatic mutations during normal aging. Here, we developed and validated TrueR sequencing to overcome next-generation sequencing-related false positives in cell-free DNA. Subsequently, TrueR identified molecular features unique to tumor-derived cell-free DNA (i.e., circulating tumor DNA) that are detectable in blood during a tumor-naïve search. Specifically, variants associated with glioblastoma circulating tumor DNA were exclusively present in cell-free DNA (i.e., absent in white blood cell DNA) and showed gene-specific subclones. These features were uncommon in low-grade glioma, stroke, and age-related somatic mosaicism of white blood cells. We also detail a variant-agnostic method, demonstrating that copy number gains and losses in short cell-free DNA fragments (<90 bp) support the detection of glioblastoma. Finally, we present evidence that our findings extend beyond glioblastoma, supporting the broader advancement of the liquid biopsy.