Lung cancer and altered brain structure: A causal inference based on MR

Lung cancer is one of the most prevalent malignancies globally and imposes a substantial burden on mortality and healthcare costs. Emerging clinical evidence suggests that lung cancer may influence brain morphology, particularly the cerebral cortex. This study employed Mendelian Randomization (MR) to investigate the potential causal relationship between lung cancer and cortical structural alterations. Single nucleotide polymorphisms associated with small cell lung cancer (SCLC) and non-SCLC (NSCLC) were instrumental variables derived from the FinnGen consortium. Summary-level data on brain cortical structures were obtained from the Enhancing Neuroimaging Genetics through Meta-Analysis consortium. MR analyses were conducted using inverse variance weighted regression, MR-Egger regression, and weighted median methods. SCLC was associated with a reduced surface area of the rostral anterior cingulate cortex (β = -0.038, 95% confidence interval [CI]: -0.057--0.019; false discovery rate-corrected P = .007). For NSCLC, we observed nominal associations with decreased cortical thickness in the paracentral (β = -0.032, 95% CI: -0.056--0.008; P = .008) and transverse temporal regions (β = -0.032, 95% CI: -0.056--0.008; P = .009), and an increased surface area of the lingual gyrus (β = 0.028, 95% CI: 0.002-0.054; P = .034). Sensitivity analyses showed no evidence of directional pleiotropy, and leave-one-out tests indicated that results were not driven by single instruments. Mediation analyses provided no support for indirect effects via insomnia, anxiety, or depression. Our findings support a causal link between SCLC and reduced rostral anterior cingulate cortex surface area and suggest additional NSCLC-related cortical alterations in sensorimotor, auditory, and visual regions. These results highlight potential neuropsychiatric and cognitive implications in lung cancer and warrant further mechanistic investigation.