Ege Ülgen1, Özge Can2, Kaya Bilguvar3,4, Cemaliye Akyerli Boylu5, Şirin Kılıçturgay Yüksel5, Ayça Erşen Danyeli6, O Uğur Sezerman1, M Cengiz Yakıcıer7, M Necmettin Pamir8, Koray Özduman9. 1. Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey. 2. Department of Medical Engineering, Faculty of Engineering, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey. 3. Department of Genetics, School of Medicine, Yale University, New Haven, CT, USA. 4. Yale Center for Genome Analysis, West Haven, CT, USA. 5. Department of Medical Biology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey. 6. Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey. 7. Department of Molecular Biology, School of Arts and Sciences, Acibadem Mehmet Ali Aydinlar University Istanbul, Istanbul, Turkey. 8. Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Altunizade Mahallesi, Yurtcan Sok. No:1, Üsküdar, Istanbul, 34662, Turkey. 9. Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Altunizade Mahallesi, Yurtcan Sok. No:1, Üsküdar, Istanbul, 34662, Turkey. Koray.ozduman@icloud.com.
Abstract
BACKGROUND: In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. METHODS: The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. RESULTS: The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14-33) variants per patient was reported. There was a median of 6 (0-590) reported somatic short variants per tumor. A median of 19 (0-94) broad SCNAs and a median of 6 (0-12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%). CONCLUSIONS: We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.
BACKGROUND: In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. METHODS: The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. RESULTS: The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14-33) variants per patient was reported. There was a median of 6 (0-590) reported somatic short variants per tumor. A median of 19 (0-94) broad SCNAs and a median of 6 (0-12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%). CONCLUSIONS: We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.
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