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Plasma Circulating Tumor DNA Assessment Reveals KMT2D As A Li et al. Biomarker Research (2020) 8:27 https://doi.org/10.1186/s40364-020-00205-4 RESEARCH Open Access Plasma circulating tumor DNA assessment reveals KMT2D as a potential poor prognostic factor in extranodal NK/T-cell lymphoma Qiong Li1,2†, Wei Zhang1,2†, Jiali Li1,2, Jingkang Xiong1,2, Jia Liu1,2, Ting Chen1,2, Qin Wen1,2, Yunjing Zeng1,2, Li Gao1,2, Lei Gao1,2, Cheng Zhang1,2, Peiyan Kong1,2, Xiangui Peng1,2, Yao Liu1,2*, Xi Zhang1,2* and Jun Rao1,2* Abstract Background: The early detection of tumors upon initial diagnosis or during routine surveillance is important for improving survival outcomes. Here, we investigated the feasibility and clinical significance of circulating tumor DNA (ctDNA) detection for Extranodal NK/T-cell lymphoma, nasal type (ENTKL). Methods: The plasma ctDNA assessment was based on blood specimens collected from 65 newly diagnosed patients with ENKTL in the hematology medical center of Xinqiao Hospital. Longitudinal samples collected under chemotherapy were also included. The gene mutation spectrum of ENKTL was analyzed via next generation sequencing. Results: 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%) and NOTCH1 (7.7%). The mutation allele frequencies of ATM and JAK3 were significantly correlated with the disease stage, and mutated KMT2D, ASXL3 and JAK3 were positively correlated with the metabolic tumor burden of the patients. Compared with the tumor tissue, ctDNA profiling showed good concordance (93.75%). Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequencies of the genes. Compared with PET/CT, ctDNA has more advantages in tracking residual disease in patients. In addition, patients with mutated KMT2D had higher expression compared with those with wild type, and mutated KMT2D predicted poor prognosis. Conclusion: Our results unveil the mutation spectrum of ENKTL patients’ plasma, which can be used to monitor the disease status of the patients exactly, and KMT2D is the most frequently mutated gene with prognosis prediction value. The application of ctDNA sequencing can provide precision treatment strategies for patients. Trial registration: This study is registered with chictr.org (ChiCTR1800014813, registered 7 February, 2018- Retrospectively registered). Keywords: ENKTL, Circulating tumor DNA, Mutation allele frequency, Minimal residual disease, Prognosis * Correspondence: [email protected]; [email protected]; [email protected] †Qiong Li and Wei Zhang contributed equally to this work. 1Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. Biomarker Research (2020) 8:27 Page 2 of 12 Introduction [19–25]. ctDNA assessment acts as a dynamic marker of Extranodal NK/T-cell lymphoma, nasal type (ENTKL), is burden during treatment based on immunoglobulin an aggressive extranodal lymphoma of NK-cell or T-cell next-generation sequencing (Ig-NGS), T-cell receptor lineage, which is highly aggressive and heterogeneous gene next-generation sequencing (TCR-NGS) and can- disease, with predominance in males [1–4]. Current cer personalized profiling sequencing (CAPP-Seq). Re- treatment strategies (such as the combination of chemo- cent evidence concerning ctDNA assessment in therapy, radiotherapy, targeted therapy) can improve the peripheral T-cell lymphoma by TCR-NGS suggested that complete remission of patients, but most will ultimately ctDNA detection in T-lineage lymphoma is feasible [26]. relapse and progress [5–7]. For these patients, standard In the present study, we thoroughly determined the mo- monitoring methods, including computed tomography lecular spectrum of ctDNA mutations in ENTKL and (CT) and serum protein markers analysis upon initial characterized the correlation between ctDNA mutations diagnosis and during routine surveillance, are pivotal for and clinical factors. Paired tumor tissues and plasma therapeutic response evaluation; however, these tests samples were collected to compare the concordance be- have limitations of low sensitivity and specificity or false tween tumor DNA and ctDNA. Moreover, dynamic positivity. Therefore, there is an urgent need for a highly ctDNA mutation alterations during treatment were also sensitive, standardized and noninvasive assay that can be observed. used for detecting early relapse and/or progression of disease. Materials and methods Current treatment response criteria for non- Study design and patient selection Hodgkin lymphoma (non-HL) rely on CT scans or In this prospective cohort study, 65 patients newly diagnosed positron emission tomography (PET) scans. Imaging with ENKTL in the hematology medical center of Xinqiao scans upon initial diagnosis or recurrence can provide Hospital from February 2017 to December 2019 were en- macro overviews of the tumor volume and location, rolled (ClinicalTrials identifier: ChiCTR1800014813). All but CT scans have some limitations due to cost and consecutive patients who were deemed appropriate for this radiation exposure, and PET lacks specificity [8–10]. study during the study period were included without selec- Moreover, imaging scans cannot monitor dynamic tion. Histological diagnoses were established independently tumor response and the clonal evolution in time. by at least two experienced senior pathologists according to Therefore, clinically validated technology is needed to the WHO classification of Tumors of Hematopoietic and overcome the current monitoring treatment response Lymphoid tissue criteria. All patients underwent baseline sta- limitations. One potential biomarker for detection is ging using laboratory, radiographic, and bone marrow exam- circulating cell-free DNA (cfDNA), which comes from inations upon diagnosis. The Eastern Cooperative Oncology dying cells that release DNA fragments into circula- Group (ECOG) performance status was also assessed. The tion, and in tumor patients, some of the cfDNA pri- stage was evaluated in accordance with the Ann Arbor sta- marily originates from apoptosis and necrotic cancer ging system. The International Prognostic Index (IPI) was cells, which carry tumor-specific alterations (termed calculated based on the serum lactate dehydrogenase, circulating tumor DNA, ctDNA) [11–14]. ctDNA se- stage, extranodal status and performance status. Pa- quencing is a promising tool for the real-time moni- tient characteristics and treatment regimens of each toring of tumor progression, and its application has therapy cycle were collected from each patient. Three been explored in multiple solid tumors [15]. ctDNA healthy individuals were also recruited as control par- can reflect the temporal evolution of tumors. Current ticipants to test the accuracy of our sequencing plat- studies have shown that ctDNA detection can be used form for ctDNA profiling. All participants provided to monitor minimal residual disease and track recur- informed written consent before undergoing any rence after treatment [16, 17]. In addition, ctDNA se- study-related procedures in accordance with the Dec- quencing is a noninvasive and tumor-specific assay, laration of Helsinki. This study was approved by the and ctDNA in circulation has a half-life of less than China Ethics Committee of Registering Clinical Trials 2 h, which is more sensitive than protein biomarkers (ChiECRCT-20,180,005). and more specific than routine surveillance imaging After the initial stage assessment, all patients were given through CT scans or PET scans [18]. Thus, dynamic 6 to 8 cycles of pegaspargase-based CHOP like regimens. tracking of ctDNA would be of higher value in guid- Patients were reviewed routinely by a combination of clin- ing personalized management strategy. ical assessment and CT or fluorodeoxyglucose-PET The clinical application of ctDNA has been performed (FDG-PET) before the administration of chemotherapy. for multiple types of lymphoma, such as diffuse large B- FDG-PET was often used as an interim scan, and the cell lymphoma (DLBCL), classical HL, follicular lymph- metabolic tumor volume (MTV) was determined from the oma, multiple myeloma and peripheral T-cell lymphoma initial and interim PET images using PET Edge software Li et al. Biomarker Research (2020) 8:27 Page 3 of 12 (MIMSoftware Inc., Cleveland, OH, USA). Serial ctDNA sequence alignment software.
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