Genetic susceptibility loci of lung cancer are associated with malignant risk of pulmonary nodules and improve malignancy diagnosis based on CEA levels

Abstract

Objective: The heightened prevalence of pulmonary nodules (PN) has escalated its significance as a public health concern. While the precise identification of high-risk PN carriers for malignancy remains an ongoing challenge, genetic variants hold potentials as determinants of disease susceptibility that can aid in diagnosis. Yet, current understanding of the genetic loci associated with malignant PN (MPN) risk is limited.

Methods: A frequency-matched case-control study was performed, comprising 247 MPN cases and 412 benign NP (BNP) controls. We genotyped 11 established susceptibility loci for lung cancer in a Chinese cohort. Loci associated with MPN risk were utilized to compute a polygenic risk score (PRS). This PRS was subsequently incorporated into the diagnostic evaluation of MPNs, with emphasis on serum tumor biomarkers.

Results: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G were identified as being associated with an increased risk of MPNs. The PRS, formulated from the cumulative risk effects of these loci, correlated with the malignant risk of PNs in a dose-dependent fashion. A high PRS was found to amplify the MPN risk by 156% in comparison to a low PRS [odds ratio (OR)=2.56, 95% confidence interval (95% CI), 1.40-4.67]. Notably, the PRS was observed to enhance the diagnostic accuracy of serum carcinoembryonic antigen (CEA) in distinguishing MPNs from BPNs, with diagnostic values rising from 0.716 to 0.861 across low- to high-PRS categories. Further bioinformatics investigations pinpointed rs10429489G>A as an expression quantitative trait locus.

Conclusions: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G contribute to MPN risk and augment the diagnostic precision for MPNs based on serum CEA concentrations.

Keywords: Pulmonary nodules; diagnosis; polygenic risk score; serum tumor biomarkers; susceptible loci.

Figure 1

Impact of polygenic risk score on diagnostic value of MPNs using serum tumor biomarkers. (A−E) Differences in serum level of CEA (A), CA19-9 (B), NSE (C), SCCA (D), and CYFRA21-1 (E) among MPN cases and BPN controls; (F) ROC curves for tumor biomarkers on distinguishing MPNs from BPNs; (G,H) ROC curves for CEA (G) and CA19-9 (H) on distinguishing MPNs from BPNs in individuals with different PRS. MPN, malignant pulmonary nodule; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; NSE, neuron-specific enolase; SCCA, squamous cell carcinoma antigen; CYFRA21-1, cytokeratin 19 fragment; BPN, benign pulmonary nodule; ROC, receiver operating characteristic; PRS, polygenic risk score; n.s., non-significant. Data are presented as . *, P<0.05; ***, P<0.001; P values were calculated by the Mann-Whitney test.

Figure 2

Expression quantitative trait loci (eQTL) analysis of candidate SNPs. (A) rs10429489G>A with P=0.005; (B) rs17038564A>G with P=0.683; (C) rs12265047A>G with P=0.837.