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Item Autoantibodies neutralizing type I IFNs are present in similar to 4\% of uninfected individuals over 70 years old and account for similar to 20\% of COVID-19 deaths(AMER ASSOC ADVANCEMENT SCIENCE, 2021-01-01) Bastard, Paul; Gervais, Adrian; Le Voyer, Tom; Rosain, Jeremie; Philippot, Quentin; Manry, Jeremy; Michailidis, Eleftherios; Hoffmann, Hans-Heinrich; Eto, Shohei; Garcia-Prat, Marina; Bizien, Lucy; Parra-Martinez, Alba; Yang, Rui; Haljasmagi, Liis; Migaud, Melanie; Sarekannu, Karita; Maslovskaja, Julia; de Prost, Nicolas; Tandjaoui-Lambiotte, Yacine; Luyt, Charles-Edouard; Amador-Borrero, Blanca; Gaudet, Alexandre; Poissy, Julien; Morel, Pascal; Richard, Pascale; Cognasse, Fabrice; Troya, Jesus; Trouillet-Assant, Sophie; Belot, Alexandre; Saker, Kahina; Garcon, Pierre; Riviere, Jacques G.; Lagier, Jean-Christophe; Gentile, Stephanie; Rosen, Lindsey B.; Shaw, Elana; Morio, Tomohiro; Tanaka, Junko; Dalmau, David; Tharaux, Pierre-Louis; Sene, Damien; Stepanian, Alain; Megarbane, Bruno; Triantafyllia, Vasiliki; Fekkar, Arnaud; Heath, James R.; Franco, Jose Luis; Anaya, Juan-Manuel; Sole-Violan, Jordi; Imberti, Luisa; Biondi, Andrea; Bonfanti, Paolo; Castagnoli, Riccardo; Delmonte, Ottavia M.; Zhang, Yu; Snow, Andrew L.; Holland, Steven M.; Biggs, Catherine M.; Moncada-Velez, Marcela; Arias, Andres Augusto; Lorenzo, Lazaro; Boucherit, Soraya; Coulibaly, Boubacar; Anglicheau, Dany; Planas, Anna M.; Haerynck, Filomeen; Duvlis, Sotirija; Nussbaum, Robert L.; Ozcelik, Tayfun; Keles, Sevgi; Bousfiha, Ahmed A.; El Bakkouri, Jalila; Ramirez-Santana, Carolina; Paul, Stephane; Pan-Hammarstrom, Qiang; Hammarstrom, Lennart; Dupont, Annabelle; Kurolap, Alina; Metz, Christine N.; Aiuti, Alessandro; Casari, Giorgio; Lampasona, Vito; Ciceri, Fabio; Barreiros, Lucila A.; Dominguez-Garrido, Elena; Vidigal, Mateus; Zatz, Mayana; van de Beek, Diederik; Sahanic, Sabina; Tancevski, Ivan; Stepanovskyy, Yurii; Boyarchuk, Oksana; Nukui, Yoko; Tsumura, Miyuki; Vidaur, Loreto; Tangye, Stuart G.; Burrel, Sonia; Duffy, Darragh; Quintana-Murci, Lluis; Klocperk, Adam; Kann, Nelli Y.; Shcherbina, Anna; Lau, Yu-Lung; Leung, Daniel; Coulongeat, Matthieu; Marlet, Julien; Koning, Rutger; Reyes, Luis Felipe; Chauvineau-Grenier, Angelique; Venet, Fabienne; Monneret, Guillaume; Nussenzweig, Michel C.; Arrestier, Romain; Boudhabhay, Idris; Baris-Feldman, Hagit; Hagin, David; Wauters, Joost; Meyts, Isabelle; Dyer, Adam H.; Kennelly, Sean P.; Bourke, Nollaig M.; Halwani, Rabih; Sharif-Askari, Narjes Saheb; Dorgham, Karim; Sallette, Jerome; Sedkaoui, Souad Mehlal; AlKhater, Suzan; Rigo-Bonnin, Raul; Morandeira, Francisco; Roussel, Lucie; Vinh, Donald C.; Ostrowski, Sisse Rye; Condino-Neto, Antonio; Prando, Carolina; Bondarenko, Anastasiia; Spaan, Andras N.; Gilardin, Laurent; Fellay, Jacques; Lyonnet, Stanislas; Bilguvar, Kaya; Lifton, Richard P.; Mane, Shrikant; Anderson, Mark S.; Boisson, Bertrand; Beziat, Vivien; Zhang, Shen-Ying; Andreakos, Evangelos; Hermine, Olivier; Pujol, Aurora; Peterson, Part; Mogensen, Trine H.; Rowen, Lee; Mond, James; Debette, Stephanie; de Lamballerie, Xavier; Duval, Xavier; Mentre, France; Zins, Marie; Soler-Palacin, Pere; Colobran, Roger; Gorochov, Guy; Solanich, Xavier; Susen, Sophie; Martinez-Picado, Javier; Raoult, Didier; Vasse, Marc; Gregersen, Peter K.; Piemonti, Lorenzo; Rodriguez-Gallego, Carlos; Notarangelo, Luigi D.; Su, Helen C.; Kisand, Kai; Okada, Satoshi; Puel, Anne; Jouanguy, Emmanuelle; Rice, Charles M.; Tiberghien, Pierre; Zhang, Qian; Cobat, Aurelie; Abel, Laurent; Casanova, Jean-Laurent; Lab, H. G. I. D.; Clinicians, C. O. V. I. D.; Clinicians, C. O. V. I. D.-S. T. O. R. M.; Grp, N.I.A.I.D. Immune Response Covid; Grp, N. H.-C.O.V.A.I.R. Study; Danish, C. H. G. E.; Study, Danish Blood Donor; Interest, St Jamess Hosp Sars CoV2; Grp, French C.O.V.I.D. Cohort Study; COVID-Grp, Imagine; Consortium, Milieu Interieur; Cohort, CoV-Contact; Inv, Amsterdam Umc Covid-19 Biobank; Efft, C.O.V.I.D. Human Genetic; Cohort, C. O. N. S. T. A. N. C. E. S.; Study, 3C.-Dijon; HealthCare, Cerba; Grp, Etab Sang StudyCirculating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mlItem The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies(NATL ACAD SCIENCES, 2022-01-01) Manry, Jeremy; Bastard, Paul; Gervais, Adrian; Le Voyer, Tom; Rosain, Jeremie; Philippot, Quentin; Michailidis, Eleftherios; Hoffmann, Hans-Heinrich; Eto, Shohei; Garcia-Prat, Marina; Bizien, Lucy; Parra-Martinez, Alba; Yang, Rui; Haljasmagi, Liis; Migaud, Melanie; Sarekannu, Karita; Maslovskaja, Julia; de Prost, Nicolas; Tandjaoui-Lambiotte, Yacine; Luyt, Charles-Edouard; Amador-Borrero, Blanca; Gaudet, Alexandre; Poissy, Julien; Morel, Pascal; Richard, Pascale; Cognasse, Fabrice; Troya, Jesus; Trouillet-Assant, Sophie; Belot, Alexandre; Saker, Kahina; Garcon, Pierre; Riviere, Jacques G.; Lagier, Jean-Christophe; Gentile, Stephanie; Rosen, Lindsey B.; Shaw, Elana; Morio, Tomohiro; Tanaka, Junko; Dalmau, David; Tharaux, Pierre-Louis; Sene, Damien; Stepanian, Alain; Megarbane, Bruno; Triantafyllia, Vasiliki; Fekkar, Arnaud; Heath, James R.; Franco, Jose Luis; Anaya, Juan-Manuel; Sole-Violan, Jordi; Imberti, Luisa; Biondi, Andrea; Bonfanti, Paolo; Castagnoli, Riccardo; Delmonte, Ottavia M.; Zhang, Yu; Snow, Andrew L.; Holland, Steven M.; Biggs, Catherine M.; Moncada-Velez, Marcela; Arias, Andres Augusto; Lorenzo, Lazaro; Boucherit, Soraya; Anglicheau, Dany; Planas, Anna M.; Haerynck, Filomeen; Duvlis, Sotirija; Ozcelik, Tayfun; Keles, Sevgi; Bousfiha, Ahmed A.; El Bakkouri, Jalila; Ramirez-Santana, Carolina; Paul, Stephane; Pan-Hammarstrom, Qiang; Hammarstrom, Lennart; Dupont, Annabelle; Kurolap, Alina; Metz, Christine N.; Aiuti, Alessandro; Casari, Giorgio; Lampasona, Vito; Ciceri, Fabio; Barreiros, Lucila A.; Dominguez-Garrido, Elena; Vidigal, Mateus; Zatz, Mayana; van de Beek, Diederik; Sahanic, Sabina; Tancevski, Ivan; Stepanovskyy, Yurii; Boyarchuk, Oksana; Nukui, Yoko; Tsumura, Miyuki; Vidaur, Loreto; Tangye, Stuart G.; Burrel, Sonia; Duffy, Darragh; Quintana-Murci, Lluis; Klocperk, Adam; Kann, Nelli Y.; Shcherbina, Anna; Lau, Yu-Lung; Leung, Daniel; Coulongeat, Matthieu; Marlet, Julien; Koning, Rutger; Reyes, Luis Felipe; Chauvineau-Grenier, Angelique; Venet, Fabienne; Monneret, Guillaume; Nussenzweig, Michel C.; Arrestier, Romain; Boudhabhay, Idris; Baris-Feldman, Hagit; Hagin, David; Wauters, Joost; Meyts, Isabelle; Dyer, Adam H.; Kennelly, Sean; Bourkeh, Nollaig M.; Halwan, Rabih; Sharif-Askar, Fatemeh Saheb; Dorgham, Karim; Sallette, Jerome; Sedkaoui, Souad Mehlal; AlKhater, Suzan; Rigo-Bonnin, Raul; Morandeira, Francisco; Roussel, Lucie; Vinh, Donald C.; Erikstrup, Christian; Condino-Neto, Antonio; Prando, Carolina; Bondarenko, Anastasiia; Spaan, Andras N.; Gilardin, Laurent; Fellay, Jacques; Lyonnet, Stanislas; Bilguvar, Kaya; Lifton, Richard P.; Mane, Shrikant; Anderson, Mark S.; Boisson, Bertrand; Beziat, Vivien; Zhang, Shen-Ying; Andreakos, Evangelos; Hermine, Olivier; Pujol, Aurora; Peterson, Part; Mogensen, Trine H.; Rowen, Lee; Mond, James; Debette, Stephanie; de Lamballerie, Xavier; Burdet, Charles; Bouadma, Lila; Zins, Marie; Soler-Palacin, Pere; Colobran, Roger; Gorochov, Guy; Solanich, Xavier; Susen, Sophie; Martinez-Picado, Javier; Raoult, Didier; Vasse, Marc; Gregersen, Peter K.; Piemonti, Lorenzo; Rodriguez-Gallego, Carlos; D Notarangelo, Luigi; Su, Helen C.; Kisand, Kai; Okada, Satoshi; Puel, Anne; Jouanguy, Emmanuelle; Rice, Charles M.; Tiberghien, Pierre; Zhang, Qian; Casanova, Jean-Laurent; Abel, Laurent; Cobat, Aurelie; Lab, H. G. I. D.; Clinicians, C. O. V. I. D.; Clinicians, C. O. V. I. D.-S. T. O. R. M.; Grp, N.I.A.I.D. Immune Response C. O. V. I. D.; Grp, N. H.-C.O.V.A.I.R. Study; Danish, C. H. G. E.; Study, Danish Blood Donor; Hosp, St Jamess; Grp, French C.O.V.I.D. Cohort Study; COVID-Grp, Imagine; Consortium, Milieu Interieur; Cohort, CoV-Contact; Biobank, Amsterdam U.M.C. Covid-19; Effort, C.O.V.I.D. Human Genetic; Grp, C. P.-C. O. V. I. D.-19; Cohort, C. O. N. S. T. A. N. C. E. S.; Study, 3C.-Dijon; Hlth-Care, Cerba; Grp, Etab Francais Sang StudySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-alpha, IFN-omega, and/or IFN-beta are found in similar to 20\% of deceased patients across age groups, and in similar to 1\% of individuals aged <70 y and in >4\% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-alpha 2 or IFN-omega, the RRDs were 17.0 (95\% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and >= 70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17\% (0.12 to 0.31) for individuals <40 y old to 26.7\% (20.3 to 35.2) for those >= 80 y old for autoantibodies neutralizing IFN-alpha 2 or IFN-omega, and from 0.84\% (0.31 to 8.28) to 40.5\% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-alpha 2 and IFN-omega. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.Item Biallelic loss of human CTNNA2, encoding alpha N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration(NATURE PUBLISHING GROUP, 2018-01-01) Schaffer, Ashleigh E.; Breuss, Martin W.; Caglayan, Ahmet Okay; Al-Sanaa, Nouriya; Al-Abdulwahed, Hind Y.; Kaymakcalan, Hande; Yilmaz, Cahide; Zaki, Maha S.; Rosti, Rasim O.; Copeland, Brett; Baek, Seung Tae; Musaev, Damir; Scott, Eric C.; Ben-Omran, Tawfeg; Kariminejad, Ariana; Kayserili, Hulya; Mojahedi, Faezeh; Kara, Majdi; Cai, Na; Silhavy, Jennifer L.; Elsharif, Seham; Fenercioglu, Elif; Barshop, Bruce A.; Kara, Bulent; Wang, Rengang; Stanley, Valentina; James, Kiely N.; Nachnani, Rahul; Kalur, Aneesha; Megahed, Hisham; Incecik, Faruk; Danda, Sumita; Alanay, Yasemin; Faqeih, Eissa; Melikishvili, Gia; Mansour, Lobna; Miller, Ian; Sukhudyan, Biayna; Chelly, Jamel; Dobyns, William B.; Bilguvar, Kaya; Abou Jamra, Rami; Gunel, Murat; Gleeson, Joseph G.Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding alpha N-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The alpha N-catenin paralog, alpha E-catenin, acts as a switch regulating the balance between beta-catenin and Arp2/3 actin filament activities(1). Loss of alpha N-catenin did not affect beta-catenin signaling, but recombinant alpha N-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of alpha N-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.Item 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, JenniferBackground. We and others have identified mutually exclusive molecular subgroups of meningiomasItem The Essential Role of Centrosomal NDE1 in Human Cerebral Cortex Neurogenesis(CELL PRESS, 2011-01-01) Bakircioglu, Mehmet; Carvalho, Ofelia P.; Khurshid, Maryam; Cox, James J.; Tuysuz, Beyhan; Barak, Tanyeri; Yilmaz, Saliha; Caglayan, Okay; Dincer, Alp; Nicholas, Adeline K.; Quarrell, Oliver; Springell, Kelly; Karbani, Gulshan; Malik, Saghira; Gannon, Caroline; Sheridan, Eamonn; Crosier, Moira; Lisgo, Steve N.; Lindsay, Susan; Bilguvar, Kaya; Gergely, Fanni; Gunel, Murat; Woods, C. GeoffreyWe investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10\% of expected size (<= 10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination tinicrolissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684\_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684\_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.Item 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, MuratGliomas 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.Item 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, KorayLittle 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.Item 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, MuratBackground. 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.Item 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, KorayBackground 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.