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Genomic Profile Of Lee et al. BMC Med Genomics (2020) 13:171 https://doi.org/10.1186/s12920-020-00819-5 RESEARCH ARTICLE Open Access Genomic profle of MYCN non-amplifed neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma Eunjin Lee1†, Ji Won Lee2† , Boram Lee1,3†, Kyunghee Park1, Joonho Shim1,3, Keon Hee Yoo2, Hong Hoe Koo2, Ki Woong Sung2* and Woong‑Yang Park1,3,4* Abstract Background: MYCN amplifcation is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non‑amplifed NB including low‑ and intermediate‑risk NB. Here, the genomic characteristics of MYCN non‑amplifed NB were studied to allow for the identifcation of biomarkers for molecular stratifcation. Methods: Fifty‑eight whole exome sequencing (WES) and forty‑eight whole transcriptome sequencing (WTS) sam‑ ples of MYCN non‑amplifed NB were analysed. Forty‑one patients harboured WES and WTS pairs. Results: In the MYCN non‑amplifed NB WES data, maximum recurrent mutations were found in MUC4 (26%), fol‑ lowed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32‑CBX3 (10%) and SAMD5‑SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non‑high‑risk patients with ganglioneuroblastoma histology. Analysis of risk‑group‑specifc biomarkers showed that several genes and gene sets were diferentially expressed between the risk groups, and some immune‑related pathways tended to be activated in the high‑risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high‑risk patients had signifcantly higher levels of TMB compared with the non‑high‑risk patients. Conclusions: This study provides novel insights into the genomic background of MYCN non‑amplifed NB. Activation of immune‑related pathways in the high‑risk group and the results of TMB and mutational signature analyses collec‑ tively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB. *Correspondence: [email protected]; [email protected] †Eunjin Lee, Ji Won Lee and Boram Lee have contributed equally to this work 1 Samsung Genome Institute, Samsung Medical Center, 81 Irwon‑ro, Gangnam‑gu, Seoul 06351, Republic of Korea 2 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon‑ro, Gangnam‑gu, Seoul 06351, Republic of Korea 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://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lee et al. BMC Med Genomics (2020) 13:171 Page 2 of 11 Keywords: MYCN non‑amplifed neuroblastoma, Tumour mutation burden, Mutational signature, Genomic profle, Immunotherapy Background Samsung Medical Center Bio Bank were also included. Neuroblastoma (NB), the most common extracranial Medical records regarding age, sex, stage, risk group, solid tumour in children, accounts for 6 to 10% of all pathology, and outcome were collected. Tumour stag- childhood cancers. NB arises from precursor cells of ing was determined by following the International the sympathetic nervous system and adrenal medulla Neuroblastoma Staging System standards [2]. MYCN [1]. Te clinical course is highly heterogeneous, ranging amplifcation was determined by performing interphase from spontaneous regression without therapeutic inter- fuorescence in situ hybridization on tumour tissues. vention to rapid progression to death, despite modern Patients older than 18 months and in stage four malig- intensive multimodal treatment regimens. Tus, clinical nancy and patients with MYCN-amplifed tumours were and biological factor-based risk stratifcation and tai- stratifed as high-risk patients. lored treatment approaches have been the mainstay of NB treatment. International Neuroblastoma Risk Group DNA and RNA extraction (INRG) defnes the high-risk group to include patients All tumour specimens were reviewed by a pathologist with MYCN amplifed tumours and patients > 18 months to determine the percentage of viable tumours and their old with metastatic tumours [2]. adequacy for sequencing. Genomic DNA from the tissue Amplifcation of the MYCN oncogene is the frst and blood was extracted using a QIAamp DNA Mini Kit genetic marker reported to indicate highly aggressive (Qiagen, Valencia, CA, USA). Te total RNA from the and advanced-stage NB. It is observed in approximately same fresh frozen tumour tissues was extracted with an 20% of cases and remains a powerful prognostic factor, RNeasy Mini Kit (Qiagen, Valencia, CA, USA), accord- indicating adverse clinical outcomes [3]. Te clinical fea- ing to the manufacturer’s instructions. Te quality and tures of MYCN-amplifed NB have been attributed to the quantity of extracted nucleic acids were evaluated using biological consequence of MYCN amplifcation. MYCN- Nanodrop 8000 UV–Vis spectrometer (NanoDrop Tech- amplifed tumours make up about 40% of high-risk NBs nologies Inc., Wilmington, DE, USA), Qubit ® 3.0 Fluo- [4], indicating that 60% of high-risk NBs are MYCN rometer (Life technologies Inc., Carlsbad, CA, USA) non-amplifed tumours. Despite the extensive study of and 4200 TapeStation (Agilent Technologies Inc., Santa the genomic characteristics of high-risk NB including Clara, CA, USA). Specimens with a yield over 100 ng MYCN-amplifed tumours [4–6], genomic profling of were selected for whole exome sequencing (WES) and MYCN non-amplifed NB, including low- and intermedi- whole transcriptome sequencing (WTS). Tose with a ate-risk NB, has been limited. median DNA fragment size of 350 bp and an RNA integ- Immunotherapy, which includes the use of immune rity number (RIN) of 5 were selected. checkpoint inhibitors, has become a potential thera- peutic option, especially in adult oncology, and tumour WES and variant calling mutational burden (TMB) is known to be a predictive Tumour and matched normal DNA were enriched for marker for immunotherapy in many studies [7, 8]. How- exon regions, using the SureSelect XT regent kit (Agilent ever, except for a monoclonal antibody that acts against Technologies Inc., Santa Clara, CA, USA) and SureSelect the tumour-associated disialoganglioside, GD2 [9], lit- XT Human All Exon V5 kit (Agilent Technologies Inc., tle is known about immunotherapy in NB. Here, we Santa Clara, CA, USA). Te libraries were pooled, dena- examined the genomic profles of MYCN non-amplifed tured, and sequenced in 100-bp paired-end mode using NB and studied risk-group-specifc biomarkers, TMB, the HiSeq Rapid SBS Kit v2 (200 Cycles) and HiSeq® and mutational signature to identify biomarkers for the Rapid PE Cluster Kit v2 in Illumina HiSeq 2500 plat- molecular stratifcation of NB. forms (Illumina Technologies Inc., San Diego, CA, USA). Te mean target coverages were 166 × in tumours and Methods 104 × in normal blood. Reads were aligned to the human Study population and data collection reference genome (hg19) using the Burrows-Wheeler From November 2015, tissue and blood samples were Alignment tool (BWA) version 0.7.5a [10]. Sequence collected prospectively from NB patients undergo- Alignment and Mapping (SAM) fles were converted to ing biopsy. Samples from patients who were diagnosed Binary Alignment and Mapping (BAM) fles using SAM- before November 2015 that had been deposited at the tools (v0.1.19) [11]. Duplicate reads were removed using Lee et al. BMC Med Genomics (2020) 13:171 Page 3 of 11 Picard (version 1.128), base quality was recalibrated, 5 min at 95 °C, followed by three-step cycles of 30 s at and local realignment was optimized using Te Genome 95 °C, 30 s at 62 °C, 10 min at 72 °C, and a fnal exten- Analysis Toolkit (GATK) version 3.5 [12]. Single nucleo- sion for 20 min at 72 °C. PCR products were purifed tide variants (SNVs) and indels were identifed using using a Multiscreen flter plate (Millipore Corp., Bed- MuTect2 version 3.8.0 [13], Strelka2 version 2.8.2 [14], ford, MA, USA) and sequenced in an ABI prism 3730XL and Pindel version 0.2.5b9 [15]. Germline variants were Analyzer (Termo Fisher Scientifc, Waltham, MA, USA) identifed using HaplotypeCaller version 3.8.0 [16]. Vari- using a BigDye (R) Terminator v3.1 Cycle Sequencing ants were annotated using Ensembl Variant Efect Predic- Kit (Applied Biosystems Inc., Foster City, CA, USA). Te tor (VEP) version 87 [17]. Variants located in exons with results were accessed by Variant Reporter Software v 1.1 sufcient coverage (minimum depth of coverage ≥ 8) (Applied Biosystems Inc., Foster City, CA, USA). and a signifcant variant allele frequency (VAF ≥ 1%) were chosen for further statistical analyses. Synonymous Mutational signatures and tumour mutation burden (TMB) variants were fltered out. Read alignments were manu- A set of 30 mutational signatures, which represent dis- ally examined using Integrative Genomic Viewer (IGV) tinct characteristics of human cancer types based on base (https ://www.broad insti tute.org/igv/).
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