Original Strange Point Cake
Screening and diagnosis of early cancer patients is considered an effective strategy to reduce patient mortality, because for most cancers, if they are discovered in the early stages of development, they can be treated more effectively, which will greatly improve the survival rate of patients and reduce the burden on families and society.
Not long ago, Elizabeth Holmes, the founder of "Theranos", a "blood cancer test" company in California, was sentenced to 11 years and 3 months in prison for "fraud". This incident also reflects the current huge market demand for biomarkers for cancer screening.
Up to now, some biomarkers have been used for early screening of some tumors, such as breast cancer , prostate cancer , lung cancer, colorectal cancer and cervical cancer . These screening projects have significantly reduced the mortality rate of related diseases [1].
However, there is currently no approved biomarker for early detection of most cancer types [2].
Recently, Sinisa Bratulica, Angelo Limeta and others from Chalmers University of Technology in Sweden published their latest research results in the well-known journal PNAS.
In this study, they discovered a new metabolic cancer biomarker- free glycosaminoglycan. The biomarker can be used for early screening of 14 types of cancer. Its detection sensitivity for stage I cancer is as high as 62% and the specificity is as high as 95%. The discovery of the metabolic marker is a major complement to liquid biopsy based on genomic biomarkers, paving the way for early screening of multiple cancers [3].
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Glycosaminoglycans (GAGs) are an important component of the extracellular matrix , which mainly include: chondroitin sulfate , dermatan sulfate, keratan sulfate, heparan sulfate, heparin and hyaluronic acid , etc. Glycosaminoglycans are long-chain, linear, negatively charged polysaccharides, composed of repeating units of the disaccharide containing glycosamine, and are the most negatively charged biological macromolecules known [4]. Sinisa Bratulica et al. first conducted a case-control development study involving 553 cancer patients and 426 healthy subjects, involving a total of 14 cancer types, in which 34% of the cancer patients were classified as stage I/low grade. In total, they measured plasma free glycosaminoglycan levels in 517 cancer patients and 425 healthy subjects, and urinary free glycosaminoglycan levels in 220 cancer patients and 340 healthy subjects.
Case-control developmental study summary
Next, the researchers compared each detectable glycosaminoglycan profile (GAGomes) feature in each cancer type to baseline physiological levels in healthy subjects using a Bayesian mixed-effects linear regression model with a skewed normal response. After identifying a common GAGome signature that differs from baseline physiological levels across 14 cancer types, Sinisa Bratulica et al. explored the feasibility of using free glycosaminoglycans to differentiate cancer patients from healthy subjects. They developed three Bayesian logistic regression models using cross-validation projection predictor selection. With a specificity of 95%, the sensitivities of plasma, urine and combined GAGomes multiple cancer early detection (MCED) scores for cancer were 46.2% (95% CI: 41.9-50.6%), 66.8% (95% CI: 60.2-73.0%) and 65.8% (95% CI: 58.4-72.6%) respectively. With a specificity of 99%, the sensitivities of plasma, urine and combined GAGomes for early detection of multiple cancers were 25.7% (95% CI: 22.0-29.7%), 25.0% (95% CI: 19.4-31.3%) and 35.3% (95% CI: 28.4-42.7%) respectively.
Free glycosaminoglycans may be used for early screening of multiple cancers
In the stage I/low-grade cancer subpopulation, 95% specificity was 41.6% for plasma (95% CI: 34.2 to 49.2%) and 62.3% for urine (95%). CI: 47.9 to 75.2%), and combined plasma and urine sensitivity was 61.4% (95% CI: 45.5 to 75.6%). All three MCED scores showed a weak correlation between free GAGomes changes and tumor stage, with a slight increase in sensitivity in stage II compared with stage I, and a further increase in sensitivity in stage III compared with stage I. Taken together, these findings indicate that free glycosaminoglycans differ significantly from physiological levels in early and late cancers and could be exploited for MCED. Since the spectrum of free GAGomes is different in different cancer types, we next explored whether the above model could be used to identify different cancer types. In a test set of N=74, the model identified different cancer types with an accuracy of 74.3% (95% CI: 68.1-80.3%). Meanwhile, survival analysis showed that patients with undetected free GAGomes MCED scores had better prognosis and less aggressive cancer phenotypes compared with high-risk groups with undetected free GAGomes MCED scores.
Survival curves of cancer patients with different GAGomes MCED scores
Based on the above research results, Sinisa Bratulica et al. conducted a prospective cohort-based case-control study, including 171 subjects diagnosed with cancer within 18 months of baseline follow-up, and 110 age-, gender-, and biochemically matched subjects who remained cancer-free during follow-up.
Validation of the GAGomes MCED score for predicting cancer
Data results showed that the GAGomes MCED score in diagnosed cancer cases was higher than that in healthy controls, Its AUC for predicting cancer diagnosis within 18 months after baseline follow-up was 0.65 (95% CI: 0.58-0.72). The GAGomes MCED score has similar performance in differentiating different cancer types. The AUC of non-small cell lung cancer is 0.71 (95% CI: 0.59-0.82), and the AUC of gynecological cancer is 0.58 (95% CI: 0.40-0.75). Finally, the researchers explored whether changes in the levels of free glycosaminoglycans in mice are related to the development of cancer. Through longitudinal measurements of urine and plasma free glycosaminoglycans in mice induced with renal adenocarcinoma tumor cells in situ, they found that changes in plasma free GAGomes and urine free GAGomes levels were consistent with tumor progression from baseline (day 0) to local growth (day 6) to postoperative resection (day 8) to metastasis (day 20), which is also consistent with patterns observed in human cancer samples.
Changes in free glycosaminoglycans in plasma and urine during cancer progression in mice
Based on the above data, Sinisa Bratulica et al. proposed that it is feasible to use free glycosaminoglycans as biomarkers to screen multiple tumors in the future, which can greatly complement liquid biopsies based on genomic biomarkers and pave the way for multi-modal early detection methods of multiple cancers. This approach will further increase sensitivity to stage I cancers, with the goal of significantly reducing cancer mortality through early detection and early treatment.
