Genomic Profiling of Plasma Circulating Tumor DNA Reveals Genetics and Residual Disease in Extranodal NK/T-Cell Lymphoma

Extranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis, early detection of tumor at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising non-invasive tool for monitoring disease status. Here, we assessed the gene mutation spectrum of plasma ctDNA in ENKTL by CAPP-Seq, we found that the mostly frequently mutated genes were MGA (33.3%), TP53 (30%), ASXL3 (28.3%), DDX3X (25%), BCORL1 (25%), TRAF3 (21.7%), NOTCH3 (21.7%), STAT5B (21.7%), EP300 (21.7%), APC (20%), ATM (18.3%), TNFRSF14 (16.7%), KMT2D (16.7%), EZH2 (16.7%) and SETD2 (16.7%), mutation frequency of MGA and TP53 were significantly higher in stage III-IV, and mutation of MGA, TP53, NOTCH3, et al were significantly correlated with metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed well concordance. Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequency of genes, compared with PET/CT, ctDNA has more advantage for track residual disease of the patients, in addition, we also found that patients with mutated MGA, TP53, SETD2, APC predicted poor prognosis. Collectively, our results provide evidence the proof of concept that ctDNA may serve as novel precision medicine biomarker in ENKTL. Trial Registration: ClinicalTrials identifier: ChiCTR1800014813. Funding Statement: This project was supported by grants from the National Natural Science Fund for Youth (No. 81600166), and the technique innovation and applied program of Chongqing (cstc2018jscx-msybX0052). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All participants provided informed written consent before undergoing any study-related procedures in accordance with the Declaration of Helsinki. This study was approved by China Ethics Committee of Registering Clinical Trials (ChiECRCT-20180005).