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Genetic evidence for a potential role of cytoskeleton-associated protein 2 in lung squamous cell carcinoma: a
Qiang Xie1,2, Yuzuo Lin3,4, Qingtong Wu3
1Department of Pathology, Fujian Province Second People's Hospital, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, 350000, Fujian province, China.
Background:
Cytoskeleton-associated protein 2 (CKAP2) plays a role in tumor proliferation, but its causal relationship with lung cancer remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate this association.
Methods:
Using genome-wide association and FinnGen data, we assessed the potential causal relationship between genetically predicted plasma CKAP2 levels and lung cancer risk, including its subtypes. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger and weighted median. Sensitivity analyses included leave-one-out, Cochran's Q, MR-Egger intercept, and MR-PRESSO. To assess generalizability, we replicated the forward MR analysis using an independent deCODE pQTL dataset.
Results:
Forward MR showed a nominal association between elevated CKAP2 and lung squamous cell carcinoma (LUSC) risk (IVW: OR = 1.18; 95% CI = 1.01-1.38; P = 0.033). However, this did not survive Bonferroni correction (α = 0.0125) and was not replicated in an independent deCODE dataset (OR = 0.875; P = 0.493). No significant associations were found for overall lung cancer, lung adenocarcinoma, or small cell lung cancer. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy. Reverse MR found no causal effect of lung cancer on CKAP2 levels.
Conclusions:
This study provides nominally significant genetic evidence for an association between elevated CKAP2 levels and LUSC risk, but the finding does not survive multiple-testing correction and was not replicated in an independent dataset. Further validation in larger cohorts with harmonized proteomic platforms is required before CKAP2 can be considered a therapeutic target.
