Whole-Exome Sequencing Reveals Recurrent but Heterogeneous Mutational Profiles in Sporadic WHO Grade 1 Meningiomas

María González-Tablas; Carlos Prieto; Daniel Arandia; María Jara-Acevedo; Álvaro Otero; Daniel Pascual; Laura Ruíz; Iván Álvarez-Twose; Andrés Celestino García-Montero; Alberto Orfao; María Dolores Tabernero

doi:10.3389/fonc.2021.740782

Whole-Exome Sequencing Reveals Recurrent but Heterogeneous Mutational Profiles in Sporadic WHO Grade 1 Meningiomas

Front Oncol. 2021 Nov 17:11:740782. doi: 10.3389/fonc.2021.740782. eCollection 2021.

Authors

María González-Tablas^{1

2

3}, Carlos Prieto^{1

4}, Daniel Arandia^{1

5}, María Jara-Acevedo^{1

6}, Álvaro Otero^{1

5}, Daniel Pascual^{1

5}, Laura Ruíz^{1

5}, Iván Álvarez-Twose^{7

8}, Andrés Celestino García-Montero^{1

2

8

9}, Alberto Orfao^{1

2

3

9}, María Dolores Tabernero^{1

2

3

10}

Affiliations

¹ Instituto de Investigación Biomédica de Salamanca (IBSAL), University Hospital of Salamanca, Salamanca, Spain.
² Centre for Cancer Research (Centro de Investigación del Cáncer de Salamanca (CIC)-Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro Superior de Investigaciones Científicas (CSIC)/Universidad de Salamanca (USAL), IBSAL) and Department of Medicine, University of Salamanca, Salamanca, Spain.
³ Biomedical Research Networking Centre on Cancer- Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC) (CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain.
⁴ Bioinformatics Service Servicio de Apoyo a la Investigación de la Universidad de Salamanca (NUNCLEUS), University of Salamanca, Salamanca, Spain.
⁵ Neurosurgery Service, University Hospital of Salamanca, Salamanca, Spain.
⁶ Sequencing Service Servicio de Apoyo a la Investigación de la Universidad de Salamanca (NUNCLEUS), University of Salamanca, Salamanca, Spain.
⁷ Instituto de Estudios de Mastocitosis de Castilla La Mancha, Virgen del Valle Hospital, Toledo, Spain.
⁸ Spanish Network on Mastocytosis Red Española de Mastocitosis (REMA), Salamanca, Spain.
⁹ Spanish National DNA Bank Carlos III, University of Salamanca, Salamanca, Spain.
¹⁰ Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL-IBSAL), Salamanca, Spain.

Abstract

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.

Keywords: NF2; PTEN; WHO grade 1 meningioma; cytogenetics; mutational profiles; whole exome sequencing (WES).