Noninvasive detection of any-stage cancer using free glycosaminoglycans

Abstract

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~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.

Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling

“…Although the aberrant expression profiles and metabolic turnover of HSPG or GAGs in cancer is not fully understood, several therapeutic approaches in oncology appear likely to be based on this. Recently, the analysis of soluble GAGs as valid metabolic liquid marker profiles has been developed and outlined for detecting early stages of cancer [ 33 ]. These GAGome analyses appear highly promising for future developments in the field of liquid biopsies.…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…While GAGs have established roles in normal physiology and disease, understanding the biological functions of specific GAG structures is difficult because of their great structural heterogeneity. Urine and plasma GAG profiles (GAGomes) [ 174 ] nevertheless have been useful as tumour metabolic biomarkers for early cancer detection [ 175 ].…”

Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors

“…More importantly, pathological conditions may induce much deviation from their normal distribution, as evidenced recently in liquid biopsies of different cancers. 15 …”