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Whole Exome Sequencing of a Single Osteosarcoma Case—Integrative Analysis with Whole Transcriptome RNA-Seq Data

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Whole Exome Sequencing of a Single Osteosarcoma Case—Integrative Analysis with Whole Transcriptome RNA-Seq Data Reimann et al. Human Genomics 2014, 8:20 http://www.humgenomics.com/content/8/1/20 PRIMARY RESEARCH Open Access Whole exome sequencing of a single osteosarcoma case—integrative analysis with whole transcriptome RNA-seq data Ene Reimann1,2*, Sulev Kõks1,2, Xuan Dung Ho3,4, Katre Maasalu3,5 and Aare Märtson3,5 Abstract Background: Osteosarcoma (OS) is a prevalent primary malignant bone tumour with unknown etiology. These highly metastasizing tumours are among the most frequent causes of cancer-related deaths. Thus, there is an urgent need for different markers, and with our study, we were aiming towards finding novel biomarkers for OS. Methods: For that, we analysed the whole exome of the tumorous and non-tumour bone tissue from the same patient with OS applying next-generation sequencing. For data analysis, we used several softwares and combined the exome data with RNA-seq data from our previous study. Results: In the tumour exome, we found wide genomic rearrangements, which should qualify as chromotripsis— we detected almost 3,000 somatic single nucleotide variants (SNVs) and small indels and more than 2,000 copy number variants (CNVs) in different chromosomes. Furthermore, the somatic changes seem to be associated to bone tumours, whereas germline mutations to cancer in general. We confirmed the previous findings that the most significant pathway involved in OS pathogenesis is probably the WNT/β-catenin signalling pathway. Also, the IGF1/ IGF2 and IGF1R homodimer signalling and TP53 (including downstream tumour suppressor gene EI24) pathways may have a role. Additionally, the mucin family genes, especially MUC4 and cell cycle controlling gene CDC27 may be considered as potential biomarkers for OS. Conclusions: The genes, in which the mutations were detected, may be considered as targets for finding biomarkers for OS. As the study is based on a single case and only DNA and RNA analysis, further confirmative studies are required. Keywords: Osteosarcoma, Whole exome sequencing, Integrative analysis Introduction have been made in the last decades in terms of survival. Osteosarcoma (OS) is a most prevalent primary malig- Thus, the survival plateau forces scientists to look for nant bone tumour and mostly occurs in children and new biomarkers (diagnostic, disease monitoring, re- adolescents—75% of patients with OS are 15 to 25 years sponse, resistance markers, drug targets), which could old. The etiology is unknown; however, a genetic predis- lead to, i.e. applying new therapeutic agents. While OS position has been suggested [1,2]. Reviewed in [3], these is rare and very heterogeneous (inter-patient, inter- tumours have high potential to metastasize and are one tumour and intra-tumour heterogeneity), the clinical of the most frequent causes of cancer-related deaths. study progress is slow; thus, the preclinical studies are The survival rate increased up to 70% after chemotherapy vital. Furthermore, finding the biomarkers and detect- became available [4]. However, no further improvements ing the potential targets for new drugs are essential to improve the present situation. * Correspondence: [email protected] There are several next-generation sequencing (NGS) 1Department of Pathophysiology, University of Tartu, 19 Ravila Street and genome-wide association studies (GWAS) about Tartu 50411, Estonia 2Department of Reproductive Biology, Estonian University of Life Sciences, OS, which associate different genes and pathways with 64 Kreutzwaldi Street, Tartu, Estonia pathogenesis of OS [5-7]. With whole exome sequencing Full list of author information is available at the end of the article © 2014 Reimann et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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. Reimann et al. Human Genomics 2014, 8:20 Page 2 of 16 http://www.humgenomics.com/content/8/1/20 (WES) and whole genome sequencing (WGS) studies, same patient with osteosarcoma. We used next-generation TP53, PTEN and PRB2 are found to be mutated in sig- sequencing to study how the coding region of the tumour nificant frequency [5]. High mutation rate in TP53 has genome has altered. Additionally, we analysed together also demonstrated in OS cell lines. Additionally, deletion the WES genotyping and RNA expression data (from our of CDKN2A/B locus and amplification of MDM2 were previous RNA-seq analysis). detected [8]. With GWAS studies, a single nucleotide variant (SNV) in GRM4 was detected as potential bio- Materials and methods marker for OS [7]. Gene expression studies reveal that, i. Subject e. WNT inhibitory factor (WIF1) has a loss of expression The protocols and informed consent form used in this in OS cell lines [9]; however, we found in our previous study were approved by the Ethical Review Committee work that the expression has increased significantly [10]. on Human Research of the University of Tartu. The pa- Thus, as demonstrated, the expression pattern of WNT tient signed a written informed consent, which also in- pathway genes in different OS cases may not be similar. cludes the acceptance of the report to be published. A When correlating the expression patterns of miRNA/ 16-year-old Caucasian male patient with an OS diagnosis mRNA pairs, miRNAs regulating TGFBR2, IRS1, PTEN was studied. In more detail, the patient became ill with and PI3K have been detected [11]. In addition, several complaints of pain in the left knee area. History of serine/threonine kinases (mechanistic target of rapamy- trauma was missing, and GP administered painkillers cin (mTOR)) or tyrosine kinases (SRC, IGF1R, PDGFR, and vitamins. After 6 months, the patient returned to KIT) are considered as targets in OS treatment [3,12,13]. GP with complaints of pain, swelling and dysfunction in When observing the related pathways, the WNT/β-ca- the left distal femur and knee area. The swelling line was tenin pathway is one of the most thoroughly studied observed in the left femoral distal region, and the area among bone malignancies. For example, the tumour was thicker and painful to touch. No changes in skin growth is regulated through this pathway and the over- colour were detected. The X-ray investigation showed expression of BMP9 suppresses its activity [14,15]. Fur- additional shading and structural change in the distal thermore, PI3K/AKT/mTOR signalling pathway was part of the left femur. For detailed investigation, the brought forward as a potential target for therapy, and MRI was performed and as a result, malignant process also, pathways associated to TP53 may be altered [5]. was suspected. Patient was hospitalized, and bone biopsy Hypoxia-HIF-1α-CXCR4 pathway plays a crucial role was taken for histological investigation. The diagnosis of during the migration of human osteosarcoma cells [16]. osteosarcoma was confirmed. Chemotherapy for osteo- These are just a few examples—the network of associ- sarcoma started by Scandinavian Sarcoma Group (SSG) ated genes and pathways is complex. XIV treatment protocol. The patient responded well to OS has a very unstable genome—it may contain aberrant the therapy—the histological analysis confirmed the nec- number of chromosomes, and in most cases, these chro- rotic tissue in tumour. After 3 month of chemotherapy, mosomes display major structural abnormalities including surgical removal of tumour (distal part of femoral bone amplification, deletions and translocations. For example, with knee joint) and replacement of the knee and the several studies have demonstrated the gain of chromosomal lower part of the femur with megaprosthesis was per- arms 6p, 8q and 17p in the case of OS [17,18]. To be more formed. Pathologist confirmed that resection line was precise, i.e. VEGFA amplification and LSAMP deletion have without tumour cells and OS was referred as NAS (Not been detected in OS [19,20]. Thus, it is suggested that gen- Further Specified). After the patient had recovered from omic instability is linked to the development of this tumour surgery, the SSG XIV chemotherapy treatment protocol [18,21-23]. Furthermore, the genomicaberrationsaremore was followed. Materials for this study were collected frequent in metastases than in primary tumours [24]. The from the surgically removed tissue. genes responsible for cell cycle regulation are suggested to be associated to DNA breakage and genomic instability, i.e. Exome sequencing CDC5L overexpression and mutations in TP53 gene are The genomic DNA (gDNA) was extracted from two correlated to the high genomic instability in OS [23,25]. bone samples from different locations—one sample from Moreover, the chromothripsis event is characteristic to tumour area and another sample from the uninvolved OS—it generates new fusion products. This may explain normal bone tissue as a control. For gDNA extraction, the sudden onset of OS and the complexity and heterogen- the tissue was homogenized applying liquid nitrogen and eity of OS genome [26]. All these changes make it difficult a mortar, and after that, the PureLink Genomic DNA kit to find biomarkers suitable for targeting OS, as there are so (Life Technologies Corp., Carlsbad, CA, USA) was used many different subtypes. according to manufacturer’s protocol. The Target Seq In the present work, we analysed the whole exome of Exome Enrichment System and SOLiD 5500 barcoded the tumorous and non-tumour bone tissue from the adaptors (Life Technologies Corp., Carlsbad, CA, USA) Reimann et al. Human Genomics 2014, 8:20 Page 3 of 16 http://www.humgenomics.com/content/8/1/20 were used to prepare the libraries. The SOLiD 5500xl SNVs, small indels and CNVs platform and paired-end DNA sequencing chemistry (75 bp forward and 35 bp reverse direction) were applied 1) Results from ANNOVAR software to sequence the samples.
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