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Genomic profiling of plasma circulating tumor DNA reveals genetics and residual disease in extranodal NK/T-cell lymphoma

By Qiong Li, Wei Zhang, Jiali Li, Jingkang Xiong, Jia Liu, Ting Chen, Qin Wen, Yunjing Zeng, Li Gao, Lei Gao, Cheng Zhang, Peiyan Kong, Yao Liu, Xi Zhang, Jun Rao

Posted 10 Oct 2019
bioRxiv DOI: 10.1101/800409

Background Extranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis. Early detection of tumors at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool for monitoring disease status. Here, we investigated the feasible of ctDNA detection in ENTKL. Methods Plasma ctDNA was assessment were based on blood specimens that were collected from 65 patients recently diagnosed with ENKTL at the hematology medical center of Xinqiao Hospital, longitudinal samples collected under chemotherapy also included. Gene mutation spectrum of ENKTL was analyzed via cancer personalized profiling sequencing (CAPP-Seq). This study is registered with ClinicalTrials.gov (ChiCTR1800014813) Results From February 2017 to September 2019, 65 patients were enrolled, we found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%), NOTCH1 (7.7%). The mutation frequencies of KMT2D was significantly higher in stage III-IV, and mutations in KMT2D, ASXL3 and JAK3 were significantly correlated with the metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed good 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 advantages for tracking residual disease in patients. In addition, we also found that mutated KMT2D predicted poor prognosis in patients. Conclusion Collectively, our results provide evidence that ctDNA may serve as a novel precision medicine biomarker in ENKTL. * ENTKL : Extranodal NK/T-cell lymphoma, nasal type CT : Computed tomography Non-NHL : non-Hodgkin lymphoma cfDNA : circulating cell-free DNA ctDNA : circulating tumor DNA DLBCL : diffuse large B-cell lymphoma CAPP-Seq : cancer personalized profiling sequencing MTV : metabolic tumor volume ADAM3A : ADAM Metallopeptidase Domain 3A APC : Adenomatous Polyposis Coli Protein ARID1A : AT-Rich Interaction Domain 1A ARID1B : AT-Rich Interaction Domain 1B ARID2 : AT-Rich Interaction Domain 2 ASXL3 : ASXL Transcriptional Regulator 3 ATM : Ataxia Telangiectasia Mutated BCOR : BCL6 Corepressor BCORL1 : BCL6 Corepressor Like 1 CHD8 : Chromodomain Helicase DNA Binding Protein 8 CREBBP : CREB Binding Protein DDX3X : DEAD-Box Helicase 3 X-Linked DNMT3A : DNA Methyltransferase 3 Alpha EP300 : E1A Binding Protein P300 EZH2 : Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit FYN : Src Family Tyrosine Kinase IDH2 : Isocitrate Dehydrogenase (NADP(+)) 2, Mitochondrial IL2RG : Interleukin 2 Receptor Subunit Gamma JAK1 : Janus Kinase 1 JAK3 : Janus Kinase3 KDM6A : Lysine Demethylase 6A KMT2A : Lysine Methyltransferase 2A KMT2D : Lysine Methyltransferase 2D MGA : MAX Dimerization Protein NF1 : Neurofibromin 1 NOTCH1 : Notch Receptor 1 PRDM1 : Positive Regulatory Domain I-Binding Factor 1 PTPN1 : Protein Tyrosine Phosphatase Non-Receptor Type 1 RHOA : Ras Homolog Family Member A SETD2 : SET Domain Containing 2 SOCS1 : Suppressor of Cytokine Signaling 1 STAT3 : Signal Transducer and Activator of Transcription 3 STAT5B : Signal Transducer and Activator of Transcription 5B STAT6 : Signal Transducer and Activator of Transcription 6 TET1 : Tet Methylcytosine Dioxygenase 1 TNFRSF14 : TNF Receptor Superfamily Member 14 TP53 : Tumor Protein P53 TRAF3 : TNF Receptor Associated Factor 3 ZAP608 : Zeta Chain Of T Cell Receptor Associated Protein Kinase 608 MAF : mutated allele frequency SNV : single nucleotide variant

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