Anne Guyot1, Mathilde Duchesne1, Sandrine Robert2, Anne-Sophie Lia3, Paco Derouault3, Erwan Scaon4, Leslie Lemnos5, Henri Salle5, Karine Durand1,2, François Labrousse6,7. 1. Department of Pathology, Limoges University Hospital, 2 Avenue Martin-Luther-King, 87042, Limoges, France. 2. EA 3842, CAPTuR « Contrôle de L'Activation Cellulaire, Progression Tumorale Et Résistance Thérapeutique », Faculty of Medicine, Limoges University, 2 Rue du Docteur Marcland, 87025, Limoges, France. 3. EA 6309, MMNP « Maintenance Myélinique Et Neuropathies Périphériques », Faculty of Medicine, Limoges University, 2 Rue du Docteur Marcland, 87025, Limoges, France. 4. Bioinformatics Unit, BISCEM Platform, CBRS, University of Limoges, 2 Rue du Docteur-Marcland, 87025, Limoges, France. 5. Department of Neurosurgery, Limoges University Hospital, 2 Avenue Martin-Luther-King, 87042, Limoges, France. 6. Department of Pathology, Limoges University Hospital, 2 Avenue Martin-Luther-King, 87042, Limoges, France. francois.labrousse@unilim.fr. 7. EA 3842, CAPTuR « Contrôle de L'Activation Cellulaire, Progression Tumorale Et Résistance Thérapeutique », Faculty of Medicine, Limoges University, 2 Rue du Docteur Marcland, 87025, Limoges, France. francois.labrousse@unilim.fr.
Abstract
PURPOSE: Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence. METHODS: We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data. RESULTS: We identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations-p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%-was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004). CONCLUSION: We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.
PURPOSE: Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence. METHODS: We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data. RESULTS: We identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations-p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%-was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004). CONCLUSION: We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.
Authors: Tadeusz Debniak; Rodney J Scott; Tomasz Huzarski; Tomasz Byrski; Andrzej Rozmiarek; Boguslaw Debniak; Bohdan Górski; Cezary Cybulski; Krzysztof Medrek; Marek Mierzejewski; Bartłomiej Masojc; Joanna Matyjasik; Elzbieta Złowocka; Urszula Teodorczyk; Marcin Lener; Ewa Klujszo-Grabowska; Katarzyna Nej-Wołosiak; Ewa Jaworowska; Dorota Oszutowska; Anna Szymańska; Jolanta Szymańska; Jennifer Castaneda; Thierry van de Wetering; Janina Suchy; Grzegorz Kurzawski; Oleg Oszurek; Steven Narod; Jan Lubinski Journal: Int J Cancer Date: 2006-06-15 Impact factor: 7.396
Authors: Anne Durand; François Labrousse; Anne Jouvet; Luc Bauchet; Michel Kalamaridès; Philippe Menei; Robert Deruty; Jean Jacques Moreau; Michelle Fèvre-Montange; Jacques Guyotat Journal: J Neurooncol Date: 2009-06-27 Impact factor: 4.130
Authors: J Boström; B Meyer-Puttlitz; M Wolter; B Blaschke; R G Weber; P Lichter; K Ichimura; V P Collins; G Reifenberger Journal: Am J Pathol Date: 2001-08 Impact factor: 4.307
Authors: Stephen T Magill; Charlotte D Eaton; Abrar Choudhury; Briana C Prager; William C Chen; Martha A Cady; Kyounghee Seo; Calixto-Hope G Lucas; Tim J Casey-Clyde; Harish N Vasudevan; S John Liu; Javier E Villanueva-Meyer; Tai-Chung Lam; Jenny Kan-Suen Pu; Lai-Fung Li; Gilberto Ka-Kit Leung; Danielle L Swaney; Michael Y Zhang; Jason W Chan; Zhixin Qiu; Michael V Martin; Matthew S Susko; Steve E Braunstein; Nancy Ann Oberheim Bush; Jessica D Schulte; Nicholas Butowski; Penny K Sneed; Mitchel S Berger; Nevan J Krogan; Arie Perry; Joanna J Phillips; David A Solomon; Joseph F Costello; Michael W McDermott; Jeremy N Rich; David R Raleigh Journal: Nat Genet Date: 2022-05-09 Impact factor: 41.307
Authors: Farshad Nassiri; Justin Z Wang; Karolyn Au; Jill Barnholtz-Sloan; Michael D Jenkinson; Kate Drummond; Yueren Zhou; James M Snyder; Priscilla Brastianos; Thomas Santarius; Suganth Suppiah; Laila Poisson; Francesco Gaillard; Mark Rosenthal; Timothy Kaufmann; Derek S Tsang; Kenneth Aldape; Gelareh Zadeh Journal: Neuro Oncol Date: 2022-05-04 Impact factor: 13.029
Authors: Philipp Sievers; Thomas Hielscher; Daniel Schrimpf; Damian Stichel; David E Reuss; Anna S Berghoff; Marian C Neidert; Hans-Georg Wirsching; Christian Mawrin; Ralf Ketter; Werner Paulus; Guido Reifenberger; Katrin Lamszus; Manfred Westphal; Nima Etminan; Miriam Ratliff; Christel Herold-Mende; Stefan M Pfister; David T W Jones; Michael Weller; Patrick N Harter; Wolfgang Wick; Matthias Preusser; Andreas von Deimling; Felix Sahm Journal: Acta Neuropathol Date: 2020-07-08 Impact factor: 17.088
Authors: Stephanie M Robert; Shaurey Vetsa; Arushii Nadar; Sagar Vasandani; Mark W Youngblood; Evan Gorelick; Lan Jin; Neelan Marianayagam; E Zeynep Erson-Omay; Murat Günel; Jennifer Moliterno Journal: J Neurooncol Date: 2021-11-30 Impact factor: 4.130