Browsing by Author "Ozduman, Koray"

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Analysis of Mitochondrial DNA Control Region D-Loop in Gliomas: Result of 52 Patients
(TURKISH NEUROSURGICAL SOC, 2021-01-01) Yuksel, Sirin Kilicturgay; Ozduman, Koray; Yilmaz, Engin; Pamir, M. Necmettin; Akyerli, Cemaliye B.
AIM: To investigate the effect of mitochondrial DNA (mtDNA) variants mainly in D-loop on glioma biology. MATERIAL and METHODS: Sanger sequencing of D-loop (15971-16451 bp) for 52 glioma patients was performed and the variations were statistically analyzed for gender, WHO classification, morphological grade, IDH/TERT status. RESULTS: Total of 122 variations (51 unique) were identified in 52 patients. C16223T, T16189C, T16311C and T16126C variants were frequently detected. The total variation number was statistically non-significant among the analyzed categories. When individual variants were considered, T16311C and T16224C were statistically significant for WHO classification (p=0.033), morphological grade (p=0.036) and gender (p=0.039), respectively. CONCLUSION: Total variation number in D-loop was not found to be related with clinical variables. Our data suggests that individual variants may play a critical role in glioma biology.
Associations of meningioma molecular subgroup and tumor recurrence
(OXFORD UNIV PRESS INC, 2021-01-01) Youngblood, Mark W.; Miyagishima, Danielle F.; Jin, Lan; Gupte, Trisha; Li, Chang; Duran, Daniel; Montejo, Julio D.; Zhao, Amy; Sheth, Amar; Tyrtova, Evgeniya; Ozduman, Koray; Iacoangeli, Francesco; Peyre, Matthieu; Boetto, Julien; Pease, Matthew; Avsar, Timucin; Huttner, Anita; Bilguvar, Kaya; Kilic, Turker; Pamir, M. Necmettin; Amankulor, Nduka; Kalamarides, Michel; Erson-Omay, E. Zeynep; Gunel, Murat; Moliterno, Jennifer
Background. We and others have identified mutually exclusive molecular subgroups of meningiomas
Correlation of anatomical involvement patterns of insular gliomas with subnetworks of the limbic system
(AMER ASSOC NEUROLOGICAL SURGEONS, 2022-01-01) Ulgen, Ege; Aras, Fuat Kaan; Cosgun, Erdal; Ersen-Danyeli, Ayca; Dincer, Alp; Usseli, M. Imre; Ozduman, Koray; Pamir, M. Necmettin
OBJECTIVE Gliomas frequently involve the insula both primarily and secondarily by invasion. Despite the high connectivity of the human insula, gliomas do not spread randomly to or from the insula but follow stereotypical anatomical involvement patterns. In the majority of cases, these patterns correspond to the intrinsic connectivity of the limbic system, except for tumors with aggressive biology. On the basis of these observations, the authors hypothesized that these different involvement patterns may be correlated with distinct outcomes and analyzed these correlations in an institutional cohort. METHODS Fifty-nine patients who had undergone surgery for insular diffuse gliomas and had complete demographic, pre- and postoperative imaging, pathology, molecular genetics, and clinical follow-up data were included in the analysis (median age 37 years, range 21-71 years, M/F ratio 1.68). Patients with gliomatosis and those with only minor involvement of the insula were excluded. The presence of T2-hyperintense tumor infiltration was evaluated in 12 anatomical structures. Hierarchical biclustering was used to identify co-involved structures, and the findings were correlated with established functional anatomy knowledge. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazards regression analysis (17 parameters). RESULTS The tumors involved the anterior insula (98.3\%), posterior insula (67.8\%), temporal operculum (47.5\%), amygdala (42.4\%), frontal operculum (40.7\%), temporal pole (39\%), parolfactory area (35.6\%), hypothalamus (23.7\%), hippocampus (16.9\%), thalamus (6.8\%), striatum (5.1\%), and cingulate gyrus (3.4\%). A mean 4.2 +/- 2.6 structures were involved. On the basis of hierarchical biclustering, 7 involvement patterns were identified and correlated with cortical functional anatomy (pure insular {[}11.9\%], olfactocentric {[}15.3\%], olfactoopercular {[}33.9\%], operculoinsular {[}15.3\%], striatoinsular {[}3.4\%], translimbic {[}11.9\%], and multifocal {[}8.5\%] patterns). Cox regression identified hippocampal involvement (p = 0.006) and postoperative tumor volume (p = 0.027) as significant negative independent prognosticators of overall survival and extent of resection (p = 0.015) as a significant positive independent prognosticator. CONCLUSIONS The study findings indicate that insular gliomas primarily involve the olfactocentric limbic girdle and that involvement in the hippocampocentric limbic girdle is associated with a worse prognosis.
IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
(NATURE PUBLISHING GROUP, 2016-01-01) Oktay, Yavuz; Ulgen, Ege; Can, Ozge; Akyerli, Cemaliye B.; Yuksel, Sirin; Erdemgil, Yigit; Durasi, I. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Sevin; Ozpinar, Aysel; Huse, Jason T.; Sav, M. Aydin; Flanagan, Adrienne; Gunel, Murat; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, Koray
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52
Information theory approaches to improve glioma diagnostic workflows in surgical neuropathology
(WILEY, 2022-01-01) Cevik, Lokman; Landrove, Marilyn Vazquez; Aslan, Mehmet Tahir; Khammad, Vasilii; Garagorry Guerra, Francisco Jose; Cabello-Izquierdo, Yolanda; Wang, Wesley; Zhao, Jing; Becker, Aline Paixao; Czeisler, Catherine; Rendeiro, Anne Costa; Sousa Veras, Lucas Luis; Zanon, Maicon Fernando; Reis, Rui Manuel; Matsushita, Marcus de Medeiros; Ozduman, Koray; Pamir, M. Necmettin; Danyeli, Ayca Ersen; Pearce, Thomas; Felicella, Michelle; Eschbacher, Jennifer; Arakaki, Naomi; Martinetto, Horacio; Parwani, Anil; Thomas, Diana L.; Otero, Jose Javier
Aims Resource-strained healthcare ecosystems often struggle with the adoption of the World Health Organization (WHO) recommendations for the classification of central nervous system (CNS) tumors. The generation of robust clinical diagnostic aids and the advancement of simple solutions to inform investment strategies in surgical neuropathology would improve patient care in these settings. Methods We used simple information theory calculations on a brain cancer simulation model and real-world data sets to compare contributions of clinical, histologic, immunohistochemical, and molecular information. An image noise assay was generated to compare the efficiencies of different image segmentation methods in H\&E and Olig2 stained images obtained from digital slides. An auto-adjustable image analysis workflow was generated and compared with neuropathologists for p53 positivity quantification. Finally, the density of extracted features of the nuclei, p53 positivity quantification, and combined ATRX/age feature was used to generate a predictive model for 1p/19q codeletion in IDH-mutant tumors. Results Information theory calculations can be performed on open access platforms and provide significant insight into linear and nonlinear associations between diagnostic biomarkers. Age, p53, and ATRX status have significant information for the diagnosis of IDH-mutant tumors. The predictive models may facilitate the reduction of false-positive 1p/19q codeletion by fluorescence in situ hybridization (FISH) testing. Conclusions We posit that this approach provides an improvement on the cIMPACT-NOW workflow recommendations for IDH-mutant tumors and a framework for future resource and testing allocation.
Integrated genomic characterization of IDH1-mutant glioma malignant progression
(NATURE PUBLISHING GROUP, 2016-01-01) Bai, Hanwen; Harmanci, Akdes Serin; Erson-Omay, E. Zeynep; Li, Jie; Coskun, Sueleyman; Simon, Matthias; Krischek, Boris; Ozduman, Koray; Omay, S. Buelent; Sorensen, Eric A.; Turcan, Sevin; Bakirciglu, Mehmet; Carrion-Grant, Geneive; Murray, Phillip B.; Clark, Victoria E.; Ercan-Sencicek, A. Gulhan; Knight, James; Sencar, Leman; Altinok, Selin; Kaulen, Leon D.; Guelez, Burcu; Timmer, Marco; Schramm, Johannes; Mishra-Gorur, Ketu; Henegariu, Octavian; Moliterno, Jennifer; Louvi, Angeliki; Chan, Timothy A.; Tannheimer, Stacey L.; Pamir, M. Necmettin; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; Guenel, Murat
Gliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
Longitudinal analysis of treatment-induced genomic alterations in gliomas
(BIOMED CENTRAL LTD, 2017-01-01) Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bulent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; Ozduman, Koray; Carrion-Grant, Geneive; Clark, Victoria E.; Caglar, Caner; Bakircioglu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Gunel, Murat
Background: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy
Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms
(MDPI, 2020-01-01) Ulgen, Ege; Karacan, Sila; Gerlevik, Umut; Can, Ozge; Bilguvar, Kaya; Oktay, Yavuz; B. Akyerli, Cemaliye; K. Yuksel, Sirin; E. Danyeli, Ayca; Tihan, Tarik; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, Koray
Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and ``Others{''} differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.
Oligosarcomas, IDH-mutant are distinct and aggressive
(SPRINGER, 2022-01-01) Suwala, Abigail K.; Felix, Marius; Friedel, Dennis; Stichel, Damian; Schrimpf, Daniel; Hinz, Felix; Hewer, Ekkehard; Schweizer, Leonille; Dohmen, Hildegard; Pohl, Ute; Staszewski, Ori; Korshunov, Andrey; Stein, Marco; Wongsurawat, Thidathip; Cheunsuacchon, Pornsuk; Sathornsumetee, Sith; Koelsche, Christian; Turner, Clinton; Le Rhun, Emilie; Muhlebner, Angelika; Schucht, Philippe; Ozduman, Koray; Ono, Takahiro; Shimizu, Hiroaki; Prinz, Marco; Acker, Till; Herold-Mende, Christel; Kessler, Tobias; Wick, Wolfgang; Capper, David; Wesseling, Pieter; Sahm, Felix; von Deimling, Andreas; Hartmann, Christian; Reuss, David E.
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
Oncolytic Virus Therapy for Glioblastoma Multiforme Concepts and Candidates
(LIPPINCOTT WILLIAMS \& WILKINS, 2012-01-01) Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N.
Twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding-more than 20 viruses have been recognized as potential oncolytic viruses-new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results
Pterional and Unifrontal Approaches for the Microsurgical Resection of Olfactory Groove Meningiomas: Experience with 61 Consecutive Patients
(TURKISH NEUROSURGICAL SOC, 2017-01-01) Guduk, Mustafa; Yener, Ulas; Sun, Halil Ibrahim; Hacihanefioglu, Mehmet; Ozduman, Koray; Pamir, M. Necmettin
AIM: Olfactory groove meningiomas make up 4 to 13\% of meningiomas. The first line treatment of meningiomas is surgery, but the extent and types of approaches advised for olfactory groove meningiomas are diverse, from aggressive skull base approaches to standard or minimally invasive craniotomies and endoscopic approaches. We retrospectively reviewed our series of olfactory groove meningiomas that were operated microsurgically by standard pterional or unifrontal approaches. MATERIAL and METHODS: Our series of 61 olfactory groove meningioma patients operated through pterional or unifrontal approaches between March 1987 and September 2015 was reviewed and the clinical data, radiological findings, surgical treatment and clinical outcomes of the patients were retrospectively analyzed. RESULTS: Sixty-three craniotomies were performed in total. Pterional and unifrontal approaches were used in 38 (60.3\%) and 25 (39.7\%) surgical procedures, respectively. Overall, gross total tumor resection was achieved in 59 (93.7\%) cases. Complications were seen in 8 cases, and 2 of these patients underwent reoperation. Three of the 4 patients where only subtotal resection could be achieved underwent gamma knife radiosurgery. CONCLUSION: Pterional and unifrontal approaches, which are familiar and standard for neurosurgeons, can accomplish high rates of total resection with acceptable complication and recurrence rates for the treatment of olfactory groove meningiomas.
Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma
(BMC, 2021-01-01) Ulgen, Ege; Can, Ozge; Bilguvar, Kaya; Boylu, Cemaliye Akyerli; Yuksel, Sirin Kilicturgay; Danyeli, Ayca Ersen; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, Koray
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.
Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
(OXFORD UNIV PRESS INC, 2015-01-01) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; Ozduman, Koray; Koksal, Yavuz; Li, Jie; Harmanci, Akdes Serin; Clark, Victoria; Carrion-Grant, Geneive; Baranoski, Jacob; Caglar, Caner; Barak, Tanyeri; Coskun, Suleyman; Baran, Burcin; Kose, Dogan; Sun, Jia; Bakircioglu, Mehmet; Gunel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Gunel, Murat
Background. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these ``ultramutated{''} tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.
The effect of tumor shape irregularity on Gamma Knife treatment plan quality and treatment outcome: an analysis of 234 vestibular schwannomas
(NATURE PORTFOLIO, 2022-01-01) Sumer, Esra; Tek, Ece; Ture, O. Artunc; Sengoz, Meric; Dincer, Alp; Ozcan, Alpay; Pamir, M. Necmettin; Ozduman, Koray; Ozturk-Isik, Esin
The primary aim of Gamma Knife (GK) radiosurgery is to deliver high-dose radiation precisely to a target while conforming to the target shape. In this study, the effects of tumor shape irregularity (TSI) on GK dose-plan quality and treatment outcomes were analyzed in 234 vestibular schwannomas. TSI was quantified using seven different metrics including volumetric index of sphericity (VioS). GK treatment plans were created on a single GK-Perfexion/ICON platform. The plan quality was measured using selectivity index (SI), gradient index (GI), Paddick's conformity index (PCI), and efficiency index (EI). Correlation and linear regression analyses were conducted between shape irregularity features and dose plan indices. Machine learning was employed to identify the shape feature that predicted dose plan quality most effectively. The treatment outcome analysis including tumor growth control and serviceable hearing preservation at 2 years, were conducted using Cox regression analyses. All TSI features correlated significantly with the dose plan indices (P < 0.0012). With increasing tumor volume, vestibular schwannomas became more spherical (P < 0.05) and the dose plan indices varied significantly between tumor volume subgroups (P < 0.001 and P < 0.01). VioS was the most effective predictor of GK indices (P < 0.001) and we obtained 89.36\% accuracy (79.17\% sensitivity and 100\% specificity) for predicting PCI. Our results indicated that TSI had significant effects on the plan quality however did not adversely affect treatment outcomes.