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<p>Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher costs limit its wide adoption. Here, we applied deep (~120×) lower-cost WGS (Ultima Genomics) for tumor-informed circulating tumor DNA detection within the part-per-million range. We further leveraged lower-cost sequencing by developing duplex error-corrected WGS of ccfDNA, achieving 7.7 × 10<sup>−7</sup> error rates, allowing us to assess disease burden in individuals with melanoma and urothelial cancer without matched tumor sequencing. This error-corrected WGS approach will have broad applicability across genomics, allowing for accurate calling of low-abundance variants at efficient cost and enabling deeper mapping of somatic mosaicism as an emerging central aspect of aging and disease.</p>

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Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling

  • 期刊论文

  • 发表日期：

    2025年4月11日

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  • Alexandre Pellan Cheng,
  • Adam J. Widman,
  • Anushri Arora,
  • Itai Rusinek,
  • Aaron Sossin,
  • Srinivas Rajagopalan,
  • Nicholas Midler,
  • William F. Hooper,
  • Rebecca M. Murray,
  • Daniel Halmos,
  • Theophile Langanay,
  • Hoyin Chu,
  • Giorgio Inghirami,
  • Catherine Potenski,
  • Soren Germer,
  • Melissa Marton,
  • Dina Manaa,
  • Adrienne Helland,
  • Rob Furatero,
  • Jaime McClintock,
  • Lara Winterkorn,
  • Zoe Steinsnyder,
  • Yohyoh Wang,
  • Asrar I. Alimohamed,
  • Murtaza S. Malbari,
  • Ashish Saxena,
  • Margaret K. Callahan,
  • Dennie T. Frederick,
  • Lavinia Spain,
  • Michael Sigouros,
  • Jyothi Manohar,
  • Abigail King,
  • David Wilkes,
  • John Otilano,
  • Olivier Elemento,
  • Juan Miguel Mosquera,
  • Ariel Jaimovich,
  • Doron Lipson,
  • Samra Turajlic,
  • Michael C. Zody,
  • Nasser K. Altorki,
  • Jedd D. Wolchok,
  • Michael A. Postow,
  • Nicolas Robine,
  • Bishoy M. Faltas,
  • Genevieve Boland,
  • Dan A. Landau

摘要

Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher costs limit its wide adoption. Here, we applied deep (~120×) lower-cost WGS (Ultima Genomics) for tumor-informed circulating tumor DNA detection within the part-per-million range. We further leveraged lower-cost sequencing by developing duplex error-corrected WGS of ccfDNA, achieving 7.7 × 10−7 error rates, allowing us to assess disease burden in individuals with melanoma and urothelial cancer without matched tumor sequencing. This error-corrected WGS approach will have broad applicability across genomics, allowing for accurate calling of low-abundance variants at efficient cost and enabling deeper mapping of somatic mosaicism as an emerging central aspect of aging and disease.