Associations and mediating mechanisms between lung cancer and chronic comorbidities: a matched case-control study.

Respiratory and cardio-cerebrovascular comorbidities are common in patients with lung cancer (LC), yet their clinical correlates and potential mediating mechanisms remain poorly understood. This study investigates the associations between respiratory and cardio-cerebrovascular comorbidities and LC and explores subtype-specific tumor biomarkers. A 1:1 matched case-control study was conducted at Qilu Hospital of Shandong University from April 2023 to March 2024. Conditional logistic regression models, adjusted for potential confounders, and causal mediation analysis were used to assess the associations and mediating pathways between chronic comorbidities and LC, including subtype-specific tumor biomarkers. Comorbidity data and blood biomarkers were extracted from electronic medical records. Respiratory and cardio-cerebrovascular comorbidities were significantly associated with LC (model 4: p = 0.029 and p = 0.045). After adjustment for the total number of chronic comorbidities, these associations were no longer significant (model 5: p = 0.507 and p = 0.875). Lymphocyte percentage (Lym %) and d-dimer (DDi) partially mediated both associations (single-mediator models: all p < 0.05). CYFRA21-1 was linked to respiratory comorbidities (p = 0.001), whereas PRO-GRP was associated with cardio-cerebrovascular comorbidities (p = 0.031), indicating subtype-specific patterns related to non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). LC is associated with both respiratory and cardio-cerebrovascular comorbidities, and immune- and coagulation-related biomarkers may partially mediate these associations. Total comorbidity burden shows a stronger association with LC risk than any individual comorbidity, underscoring the value of incorporating comorbidity assessment into LC risk evaluation.