Genetic/molecular alterations of meningiomas and the signaling pathways targeted

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features.This work was partially supported by grants from the Fundação para a Ciência e Tecnologia (PIC/IC/83108/2007, FCT, Portugal), Fondo de Investigaciones Sanitarias (RD12/0036/0048, Instituto de Salud Carlos III (ISCIII/FEDER), Ministerio de Sanidad y Consumo, Madrid, Spain), and Consejeria Sanidad Junta de Castilla y León, Gerencia Regional de Salud: GRS689/A/11, and Proyecto Intramural-IBSAL IB14-05. Patrícia Domingues is partially supported by a grant (SFRH/BD/64799/2009) from FCT. Maria Dolores Tabernero is supported by IECSCYL (Soria, Spain).Peer Reviewe

Whole-Exome sequencing reveals recurrent but heterogeneous mutational profiles in sporadic who grade 1 meningiomas

© 2021 González-Tablas, Prieto, Arandia, Jara-Acevedo, Otero, Pascual, Ruíz, Álvarez-Twose, García-Montero, Orfao and Tabernero.Human WHO grade 1 meningiomas are generally considered benign tumors; despite this, they account for ≈50% of all recurrent meningiomas. Currently, limited data exist about the mutational profiles of grade 1 meningiomas and patient outcome. We investigated the genetic variants present in 32 WHO grade 1 meningiomas using whole exome sequencing, and correlated gene mutational profiles with tumor cytogenetics and patient outcome. Overall, WHO grade 1 meningiomas harbored numerous and heterogeneous genetic variants, which most frequently affected the NF2 (47%) gene and to a less extent the PNMA6A (22%), TIGD1 (16%), SMO (13%), PTEN (13%), CREG2 (9%), EEF1A1 (6%), POLR2A (6%), ARID1B (3%), and FAIM3 (3%) genes. Notably, non-synonymous genetic variants of SMO and POLR2A were restricted to diploid meningiomas, whereas NF2 mutations were only found among tumors that showed -22/22q─ (with or without a complex karyotype). Based on NF2 mutations and tumor cytogenetics, four genetic profiles were defined with an impact on patient recurrence-free survival (RFS). These included (1) two good-prognosis tumor subgroups—diploid meningiomas (n=9) and isolated -22/22q─ associated with NF2 mutation (n=7)—with RFS rates at 10 y of 100%; and (2) two subgroups of poor-prognosis meningiomas—isolated -22/22q─ without NF2 mutation (n=3) and tumors with complex karyotypes (n=11)—with a RFS rate at 10 y of 48% (p=0.003). Our results point out the existence of recurrent but heterogeneous mutational profiles in WHO grade 1 meningiomas which have an impact on patient outcome.This work was supported by grants: IBY 17/00002 from IBSAL (Salamanca, Spain), GRS2132/A2020 from Junta de Castilla y León (Spain), and CB16/12/00400 from CIBER-ONC and FONDOS FEDER (Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain)

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

This is an open-access article distributed under the terms of the Creative Commons Attribution License.Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56 NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56 NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94/HLADR phenotypic profile proved to be a useful surrogate marker for NK-cell clonality.This work has been partially supported by the following grants: FIS 02/1244-FEDER, DTS 15/00119-FEDER, RTICC RD06/0020/0035-FEDER and RTICC RD12/0036/0048-FEDER from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain; SA103/03 and SA079U14 from the Consejería de Educación, Junta de Castilla y León, Valladolid, Spain. The research activities of the EuroFlow Consortium were supported by the European Commission (grant STREP EU-FP6, LSHB-CT-2006–018708, entitled ‘Flow cytometry for fast and sensitive diagnosis and follow-up of hematological malignancies’).Peer Reviewe

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

This is an open-access paper.Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138+ microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations - e.g. t(4;14) - are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity ≥98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations.This work was partially supported by grants from the Fundacion Memoria de Don Samuel Solorzano Barruso, Salamanca, Spain (FS/4-2010). The authors would also like to thank the Dr. Werner Jackstädt Foundation (Wuppertal, Germany) for grant supporting the work of Martin Schmidt-Hieber. The authors would like to thank the Cooperative Research Thematic Network (RTICs; RTICC RD06/0020/0035, RD06/0020/0006 and G03/136), MM Jevitt, SL firm, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 02/0905; 01/0089/01-02; PS09/01897) and Gerencia Regional de Salud de Castilla y León; Ayuda de Excelencia de Castilla y León, Consejeria de Educación (EDU/894/2009, GR37), and Consejería de Sanidad (557/A/10), Junta de Castilla y León, Valladolid, Spain for supporting this study. JMS is supported by a grant (CP05/00321) from the ISCIII, Ministerio de Ciencia e Innovacion, Madrid, Spain.Peer Reviewe

Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles

Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the EGFR gene, was the most frequently amplified chromosomal region – either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/EGFR gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.This work was supported by RETICC RD06/0020/0035, RD06/0020/0059 and RD12/0036/0048 grants from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, (Madrid, Spain and FONDOS FEDER), AES PI16/000476 (Instituto de Salud Carlos III, Madrid, Spain and FONDOS FEDER), GRS909A14 (JCYL) and CB16/12/00400 grant (CIBERONC, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER)

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer

Ajuts: This study was sponsored by Pfizer Inc.This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m 2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations. Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies. The online version of this article (10.1007/s11523-017-0530-5) contains supplementary material, which is available to authorized users

A detailed analysis of the Gl 486 planetary system

Full list of authors: Caballero, J. A.; Gonzalez-Alvarez, E.; Brady, M.; Trifonov, T.; Ellis, T. G.; Dorn, C.; Cifuentes, C.; Molaverdikhani, K.; Bean, J. L.; Boyajian, T.; Rodriguez, E.; Sanz-Forcada, J.; Zapatero Osorio, M. R.; Abia, C.; Amado, P. J.; Anugu, N.; Bejar, V. J. S.; Davies, C. L.; Dreizler, S.; Dubois, F.; Ennis, J.; Espinoza, N.; Farrington, C. D.; Garcia Lopez, A.; Gardner, T.; Hatzes, A. P.; Henning, Th; Herrero, E.; Herrero-Cisneros, E.; Kaminski, A.; Kasper, D.; Klement, R.; Kraus, S.; Labdon, A.; Lanthermann, C.; Le Bouquin, J-B; Lopez Gonzalez, M. J.; Luque, R.; Mann, A. W.; Marfil, E.; Monnier, J. D.; Montes, D.; Morales, J. C.; Palle, E.; Pedraz, S.; Quirrenbach, A.; Reffert, S.; Reiners, A.; Ribas, I; Rodriguez-Lopez, C.; Schaefer, G.; Schweitzer, A.; Seifahrt, A.; Setterholm, B. R.; Shan, Y.; Shulyak, D.; Solano, E.; Sreenivas, K. R.; Stefansson, G.; Stuermer, J.; Tabernero, H. M.; Tal-Or, L.; ten Brummelaar, T.; Vanaverbeke, S.; von Braun, K.; Youngblood, A.; Zechmeister, M.- This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Context. The Gl 486 system consists of a very nearby, relatively bright, weakly active M3.5 V star at just 8 pc with a warm transiting rocky planet of about 1.3 R⊕ and 3.0 M⊕. It is ideal for both transmission and emission spectroscopy and for testing interior models of telluric planets. Aims. To prepare for future studies, we aim to thoroughly characterise the planetary system with new accurate and precise data collected with state-of-the-art photometers from space and spectrometers and interferometers from the ground. Methods. We collected light curves of seven new transits observed with the CHEOPS space mission and new radial velocities obtained with MAROON-X at the 8.1 m Gemini North telescope and CARMENES at the 3.5 m Calar Alto telescope, together with previously published spectroscopic and photometric data from the two spectrographs and TESS. We also performed near-infrared interferometric observations with the CHARA Array and new photometric monitoring with a suite of smaller telescopes (AstroLAB, LCOGT, OSN, TJO). This extraordinary and rich data set was the input for our comprehensive analysis. Results. From interferometry, we measure a limb-darkened disc angular size of the star Gl 486 at θLDD = 0.390 ± 0.018 mas. Together with a corrected Gaia EDR3 parallax, we obtain a stellar radius R* = 0.339 ± 0.015 R⊕. We also measure a stellar rotation period at Prot = 49.9 ± 5.5 days, an upper limit to its XUV (5-920 A) flux informed by new Hubble/STIS data, and, for the first time, a variety of element abundances (Fe, Mg, Si, V, Sr, Zr, Rb) and C/O ratio. Moreover, we imposed restrictive constraints on the presence of additional components, either stellar or sub-stellar, in the system. With the input stellar parameters and the radial-velocity and transit data, we determine the radius and mass of the planet Gl 486 b at Rp = 1.343−0.062+0.063 R⊕ and Mp = 3.00−0.12+0.13 M⊕, with relative uncertainties of the planet radius and mass of 4.7% and 4.2%, respectively. From the planet parameters and the stellar element abundances, we infer the most probable models of planet internal structure and composition, which are consistent with a relatively small metallic core with respect to the Earth, a deep silicate mantle, and a thin volatile upper layer. With all these ingredients, we outline prospects for Gl 486 b atmospheric studies, especially with forthcoming James Webb Space Telescope (Webb) observations. © J. A. Caballero et al. 2022.CARMENES is an instrument at the Centro Astronómico Hispano en Andalucía (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSIC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Königstuhl, Institut de Ciències de l’Espai, Institut für Astrophysik Göttingen, Universidad Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the MINECO, the Deutsche Forschungsgemeinschaft (DFG) through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars”, the Klaus Tschira Stiftung, the states of Baden-Württemberg and Niedersachsen, and by the Junta de Andalucía. This work is based upon observations obtained with the Georgia State University (GSU) Center for High Angular Resolution Astronomy Array at Mount Wilson Observatory. The CHARA Array is supported by the National Science Foundation under Grant No. AST-1636624 and AST-2034336. Institutional support has been provided from the GSU College of Arts and Sciences and the GSU Office of the Vice President for Research and Economic Development. We would like to recognise the observing team, scientists, and support staff at the CHARA Array. Observation time for this work was generously allocated via discretionary time from CHARA Array director Theo ten Brumelaar and via NOIRLab community access program (proposals 2021A-0247 and 2021A-0141). MIRC-X received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant No. 639889), as well as from NASA (XRP NNX16AD43G) and NSF (AST 1909165). Data were partly collected with the 90 cm telescope at the Observatorio de Sierra Nevada operated by the Instituto de Astrofífica de Andalucía (IAA-CSIC). This work made use of observations from the Las Cumbres Observatory Global Telescope network. LCOGT observations were partially acquired via program number TAU2021A-015 of the Wise Observatory, Tel-Aviv University, Israel. We acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia, Innovación y Universidades and the ERDF through projects PID2019-109522GB-C5[1:4], PID2019-107061GB-C64, PID2019-110689RB-100, PGC2018-095317-B-C21, PGC2018-102108-B-I00, and the Centre of Excellence “Severo Ochoa” and “María de Maeztu” awards to the Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737), DFG through FOR2544 (KU 3625/2-1) and Germany’s Excellence Strategy to the Excellence Cluster ORIGINS (EXC-2094 - 390783311), European Research Council (Starting Grant 639889), Bulgarian National Science Fund through VIHREN-2021 (KP-06-DB/5), Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung / Fonds national suisse de la recherche scientifique (PZ00P2_174028), United Kingdom Science Technology and Facilities Council (630008203), NASA (80NSSC22K0117), National Science Foundation (2108465 and Graduate Research Fellowship DGE 1746045), Princeton University through the Henry Norris Russell Fellowship, Universidad La Laguna through the Margarita Salas Fellowship from the Spanish Ministerio de Universidades and under the EU Next Generation funds (UNI/551/2021-May 26), and the Generalitat de Catalunya (CERCA programme).Peer reviewe