Circulating CHI3L1/YKL-40 in lung cancer: Biomarker potential, analytical challenges, and clinical translation...

Lung cancer is the leading cause of cancer-related mortality worldwide, primarily due to inadequate early detection, which consequently leads to poor overall survival rates. Current serum tumor markers, including carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (ProGRP), exhibit limitations in terms of sensitivity, specificity, and predictive value for immunotherapy. The secreted glycoprotein chitinase-3-like protein 1 (CHI3L1/YKL-40), detectable by ELISA in serum and plasma, is a biologically plausible, research-stage, and potentially clinically relevant circulating lung cancer marker. Two meta-analyses (n > 950 patients) validated that elevated serum CHI3L1 is an independent predictor of poor survival in non-small cell (HR = 2.23) and small cell (HR = 1.45) lung cancer. There is preliminary evidence that it can predict the response to immune checkpoint inhibitors; however, this needs to be validated in a prospective study. Elevated levels of CHI3L1 in chronic obstructive pulmonary disease (COPD) and other inflammatory disorders significantly contribute to false-positive results, necessitating the use of disease-specific reference intervals for correction. To establish CHI3L1 as a clinical biomarker, it is imperative to address key technical issues, including pre-analytical sample handling, variability across ELISA platforms, biological influences such as age and chronic obstructive pulmonary disease, and the CHI3L1 promoter single nucleotide polymorphism (SNP) (rs4950928). A translational framework is proposed, which involves the standardization of multi-analytical platforms, the conduct of multi-center prospective studies, and the attainment of regulatory approval as an in vitro diagnostic tool.