Highly consistency of mutation spectrum between circulating tumor DNA and paired tissue in lung cancer patients.

Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutations are associated with drug resistance and prognosis in lung cancer; however, the consistency and clinical value of mutations between tissue and liquid samples are unknown.

Methods: Circulating tumor DNA (ctDNA) and matched tumor tissue samples from 405 advanced lung cancer patients were collected at Jilin Cancer Hospital between 2018 and 2022, and the mutation status was sequenced using next-generation sequencing based on a 520 gene panel. The viability of different mutant lung cancer cells was detected using MTT assay.

Results: mutations were detected in 46 (5.68 %) of 810 lung cancer samples, with 21 (5.19 %) of 405 plasma samples and 25 (6.17 %) of 405 matched tissues. p.Glu542Lys, p.Glu545Lys, and p.His1047Arg were the most common mutation types of in both the ctDNA and tissue samples. The concordance of mutations was 97.53 % between ctDNA and matched tissues (kappa: 0.770,  = 0.000), with sensitivity/true positive rate of 72.0 %, specificity/true negative rate of 99.2 %, and negative predictive value and positive predictive value of 0.982 and 0.857, respectively (AUC = 0.856,  = 0.000). Furthermore, the concordance of mutations was 98.26 % in lung adenocarcinoma and 96.43 % in lung squamous cell carcinoma. and were the most common concomitant mutations in ctDNA and tissues. Patients with mutations showed a high tumor mutational burden (TMB) ( < 0.001) and a significant correlation between bTMB and tTMB (r = 0.5986, P = 0.0041). For the tmut/ctDNA mut cohort, pathways alteration was associated with male sex ( = 0.022), old age ( = 0.007), and smoking ( = 0.001); tmut/ctDNA wt patients harbored clinicopathological factors of adenocarcinoma stage IV, with low PS score (≤1) and TMB.

Conclusion: This study showed that ctDNA is highly concordant and sensitive for identifying mutations, suggesting that mutation detection in liquid samples may be an alternative clinical practice for tissues.