4.8 Article

Noninvasive detection of any-stage cancer using free glycosaminoglycans

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2115328119

Keywords

cancer biomarkers; liquid biopsy; multi-cancer early detection; prognosis; metabolomics

Funding

  1. Swedish Research Council [2018-05973]
  2. Knut and Alice Wallenberg Foundation [2017.0328, 2018.0266]
  3. Cancerfonden [17 0625]
  4. Ingabritt och Arne Lundbergs Forskningsstiftelse [LU2016-0011, LU2020-0023]
  5. European Union's Horizon 2020 research and innovation program [849251]
  6. EIT Healthy 2019 Digital Sandbox [2019-DS1001-6543]
  7. VINNOVA [2016-00763]
  8. Vastra Gotaland Region
  9. Marta and Gustaf Agren Foundation
  10. Swedish government [ALFGBG-873181]
  11. Swedish country councils, the ALF-agreement [ALFGBG-873181]

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The study found that urine and plasma free glycosaminoglycan profiles (GAGomes) can serve as tumor metabolism biomarkers for early detection of multiple cancers. Machine learning models based on GAGomes can detect any cancer with high sensitivity and specificity. Undetected cancer patients had a significantly lower risk of death.
Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported similar to 10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (N-urine = 220 cancer vs. 360 healthy) and plasma (N-plasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring >= 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.

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