Top

Published in:

01-12-2019 | Meningioma | Laboratory Investigation

Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma

Authors: Anne Guyot, Mathilde Duchesne, Sandrine Robert, Anne-Sophie Lia, Paco Derouault, Erwan Scaon, Leslie Lemnos, Henri Salle, Karine Durand, François Labrousse

Published in: Journal of Neuro-Oncology | Issue 3/2019

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.

Available only for authorised users

Louis DNWO, Cavenee WK (2016) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon

Sahm F, Reuss DE, Giannini C (2018) WHO 2016 classification: changes and advancements in the diagnosis of miscellaneous primary CNS tumours. Neuropathol Appl Neurobiol 44:163–171. https://doi.org/10.1111/nan.12397 CrossRefPubMed

Yew A, Trang A, Nagasawa DT, Spasic M, Choy W, Garcia HM, Yang I (2013) Chromosomal alterations, prognostic factors, and targeted molecular therapies for malignant meningiomas. J Clin Neurosci 20:17–22. https://doi.org/10.1016/j.jocn.2012.02.007 CrossRefPubMed

Saraf S, McCarthy BJ, Villano JL (2011) Update on meningiomas. Oncologist 16:1604–1613. https://doi.org/10.1634/theoncologist.2011-0193 CrossRefPubMedPubMedCentral

Mawrin C, Perry A (2010) Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:379–391. https://doi.org/10.1007/s11060-010-0342-2 CrossRefPubMed

Burger PCSB (2007) Tumors of the central nervous system. Armed Forces Institute of Pathology, Washington

Voss KM, Spille DC, Sauerland C, Suero Molina E, Brokinkel C, Paulus W, Stummer W, Holling M, Jeibmann A, Brokinkel B (2017) The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value? J Neurooncol 133:641–651. https://doi.org/10.1007/s11060-017-2481-1 CrossRefPubMed

Durand A, Labrousse F, Jouvet A, Bauchet L, Kalamarides M, Menei P, Deruty R, Moreau JJ, Fevre-Montange M, Guyotat J (2009) WHO grade II and III meningiomas: a study of prognostic factors. J Neurooncol 95:367–375. https://doi.org/10.1007/s11060-009-9934-0 CrossRefPubMed

Guillaudeau A, Durand K, Bessette B, Chaunavel A, Pommepuy I, Projetti F, Robert S, Caire F, Rabinovitch-Chable H, Labrousse F (2012) EGFR soluble isoforms and their transcripts are expressed in meningiomas. PLoS ONE 7:e37204. https://doi.org/10.1371/journal.pone.0037204 CrossRefPubMedPubMedCentral

10.

Cheng G, Zhang L, Lv W, Dong C, Wang Y, Zhang J (2015) Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. Med Oncol 32:439. https://doi.org/10.1007/s12032-014-0439-0 CrossRefPubMed

11.

Bostrom J, Meyer-Puttlitz B, Wolter M, Blaschke B, Weber RG, Lichter P, Ichimura K, Collins VP, Reifenberger G (2001) Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159:661–669. https://doi.org/10.1016/S0002-9440(10)61737-3 CrossRefPubMedPubMedCentral

12.

Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochem Biophys Acta 1378:F115–F177. https://doi.org/10.1016/s0304-419x(98)00017-1 CrossRefPubMed

13.

Galani V, Lampri E, Varouktsi A, Alexiou G, Mitselou A, Kyritsis AP (2017) Genetic and epigenetic alterations in meningiomas. Clin Neurol Neurosurg 158:119–125. https://doi.org/10.1016/j.clineuro.2017.05.002 CrossRefPubMed

14.

Alexiou GA, Markoula S, Gogou P, Kyritsis AP (2011) Genetic and molecular alterations in meningiomas. Clin Neurol Neurosurg 113:261–267. https://doi.org/10.1016/j.clineuro.2010.12.007 CrossRefPubMed

15.

Lee Y, Liu J, Patel S, Cloughesy T, Lai A, Farooqi H, Seligson D, Dong J, Liau L, Becker D, Mischel P, Shams S, Nelson S (2010) Genomic landscape of meningiomas. Brain Pathol 20:751–762. https://doi.org/10.1111/j.1750-3639.2009.00356.x CrossRefPubMed

16.

Kim MS, Kim KH, Lee EH, Lee YM, Lee SH, Kim HD, Kim YZ (2014) Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas. J Neurosurg 121:1189–1200. https://doi.org/10.3171/2014.7.JNS132661 CrossRefPubMed

17.

Kheirollahi M, Mehr-Azin M, Kamalian N, Mehdipour P (2011) Expression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors. Med Oncol 28:7–14. https://doi.org/10.1007/s12032-009-9412-8 CrossRefPubMed

18.

Derouault P, Parfait B, Moulinas R, Barrot CC, Sturtz F, Merillou S, Lia AS (2017) 'COV'COP' allows to detect CNVs responsible for inherited diseases among amplicons sequencing data. Bioinformatics 33:1586–1588. https://doi.org/10.1093/bioinformatics/btx017 CrossRefPubMed

19.

Ewels P, Magnusson M, Lundin S, Kaller M (2016) MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32:3047–3048. https://doi.org/10.1093/bioinformatics/btw354 CrossRefPubMedPubMedCentral

20.

Cibulskis K, McKenna A, Fennell T, Banks E, DePristo M, Getz G (2011) ContEst: estimating cross-contamination of human samples in next-generation sequencing data. Bioinformatics 27:2601–2602. https://doi.org/10.1093/bioinformatics/btr446 CrossRefPubMedPubMedCentral

21.

Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807CrossRefPubMed

22.

Ranade K, Hussussian CJ, Sikorski RS, Varmus HE, Goldstein AM, Tucker MA, Serrano M, Hannon GJ, Beach D, Dracopoli NC (1995) Mutations associated with familial melanoma impair p16INK4 function. Nat Genet 10:114–116. https://doi.org/10.1038/ng0595-114 CrossRefPubMed

23.

Walker GJ, Gabrielli BG, Castellano M, Hayward NK (1999) Functional reassessment of P16 variants using a transfection-based assay. Int J Cancer 82:305–312. https://doi.org/10.1002/(sici)1097-0215(19990719)82:2%3c305:aid-ijc24%3e3.0.co;2-z CrossRefPubMed

24.

Dal Molin M, Zhang M, de Wilde RF, Ottenhof NA, Rezaee N, Wolfgang CL, Blackford A, Vogelstein B, Kinzler KW, Papadopoulos N, Hruban RH, Maitra A, Wood LD (2015) Very long-term survival following resection for pancreatic cancer is not explained by commonly mutated genes: results of whole-exome sequencing analysis. Clin Cancer Res 21:1944–1950. https://doi.org/10.1158/1078-0432.CCR-14-2600 CrossRefPubMedCentral

25.

Borkowska EM, Kruk A, Jedrzejczyk A, Rozniecki M, Jablonowski Z, Traczyk M, Constantinou M, Banaszkiewicz M, Pietrusinski M, Sosnowski M, Hamdy FC, Peter S, Catto JW, Kaluzewski B (2014) Molecular subtyping of bladder cancer using Kohonen self-organizing maps. Cancer Med 3:1225–1234. https://doi.org/10.1002/cam4.217 CrossRefPubMedPubMedCentral

26.

Hirsch P, Zhang Y, Tang R, Joulin V, Boutroux H, Pronier E, Moatti H, Flandrin P, Marzac C, Bories D, Fava F, Mokrani H, Betems A, Lorre F, Favier R, Feger F, Mohty M, Douay L, Legrand O, Bilhou-Nabera C, Louache F, Delhommeau F (2016) Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia. Nat Commun 7:12475. https://doi.org/10.1038/ncomms12475 CrossRefPubMedCentralPubMed

27.

Koulermou G, Shammas C, Vassiliou A, Kyriakides TC, Costi C, Neocleous V, Phylactou LA, Pantelidou M (2017) CDKN2A and MC1R variants found in Cypriot patients diagnosed with cutaneous melanoma. J Genet 96:155–160CrossRefPubMed

28.

Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC (1994) Germline p16 mutations in familial melanoma. Nat Genet 8:15–21. https://doi.org/10.1038/ng0994-15 CrossRefPubMed

29.

Harland M, Meloni R, Gruis N, Pinney E, Brookes S, Spurr NK, Frischauf AM, Bataille V, Peters G, Cuzick J, Selby P, Bishop DT, Bishop JN (1997) Germline mutations of the CDKN2 gene in UK melanoma families. Hum Mol Genet 6:2061–2067. https://doi.org/10.1093/hmg/6.12.2061 CrossRefPubMed

30.

Dahl C, Christensen C, Jonsson G, Lorentzen A, Skjodt ML, Borg A, Pawelec G, Guldberg P (2013) Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14 ARF and RARbeta signaling. Mol Cancer Res 11:1166–1178. https://doi.org/10.1158/1541-7786.MCR-13-0006 CrossRefPubMed

31.

Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, Gorski B, Cybulski C, Medrek K, Mierzejewski M, Masojc B, Matyjasik J, Zlowocka E, Teodorczyk U, Lener M, Klujszo-Grabowska E, Nej-Wolosiak K, Jaworowska E, Oszutowska D, Szymanska A, Szymanska J, Castaneda J, van de Wetering T, Suchy J, Kurzawski G, Oszurek O, Narod S, Lubinski J (2006) CDKN2A common variant and multi-organ cancer risk—a population-based study. Int J Cancer 118:3180–3182. https://doi.org/10.1002/ijc.21760 CrossRefPubMed

32.

Dong Y, Wang X, Yang YW, Liu YJ (2017) The effects of CDKN2A rs3731249, rs11515, and rs3088440 polymorphisms on cancer risk. Cell Mol Biol 63:40–44. https://doi.org/10.14715/cmb/2017.63.3.8 CrossRef

33.

Bakos RM, Besch R, Zoratto GG, Godinho JM, Mazzotti NG, Ruzicka T, Bakos L, Santos SE, Ashton-Prolla P, Berking C, Giugliani R (2011) The CDKN2A p. A148T variant is associated with cutaneous melanoma in Southern Brazil. Exp Dermatol 20:890–893. https://doi.org/10.1111/j.1600-0625.2011.01332.x CrossRefPubMed

34.

Spica T, Portela M, Gerard B, Formicone F, Descamps V, Crickx B, Ollivaud L, Archimbaud A, Dupin N, Wolkenstein P, Vitoux D, Lebbe C, Saiag P, Basset-Seguin N, Fargnoli MC, Grandchamp B, Peris K, Soufir N, Melan C (2006) The A148T variant of the CDKN2A gene is not associated with melanoma risk in the French and Italian populations. J Invest Dermatol 126:1657–1660. https://doi.org/10.1038/sj.jid.5700293 CrossRefPubMed

35.

Peyre M, Salaud C, Clermont-Taranchon E, Niwa-Kawakita M, Goutagny S, Mawrin C, Giovannini M, Kalamarides M (2015) PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss. Oncotarget 6:32713–32722. https://doi.org/10.18632/oncotarget.5296 CrossRefPubMedPubMedCentral

36.

Bello MJ, Aminoso C, Lopez-Marin I, Arjona D, Gonzalez-Gomez P, Alonso ME, Lomas J, de Campos JM, Kusak ME, Vaquero J, Isla A, Gutierrez M, Sarasa JL, Rey JA (2004) DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q. Acta Neuropathol 108:413–421. https://doi.org/10.1007/s00401-004-0911-6 CrossRefPubMed

37.

Amatya VJ, Takeshima Y, Inai K (2004) Methylation of p14(ARF) gene in meningiomas and its correlation to the p53 expression and mutation. Mod Pathol 17:705–710. https://doi.org/10.1038/modpathol.3800111 CrossRefPubMed

38.

Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, Okonechnikov K, Koelsche C, Reuss DE, Capper D, Sturm D, Wirsching HG, Berghoff AS, Baumgarten P, Kratz A, Huang K, Wefers AK, Hovestadt V, Sill M, Ellis HP, Kurian KM, Okuducu AF, Jungk C, Drueschler K, Schick M, Bewerunge-Hudler M, Mawrin C, Seiz-Rosenhagen M, Ketter R, Simon M, Westphal M, Lamszus K, Becker A, Koch A, Schittenhelm J, Rushing EJ, Collins VP, Brehmer S, Chavez L, Platten M, Hanggi D, Unterberg A, Paulus W, Wick W, Pfister SM, Mittelbronn M, Preusser M, Herold-Mende C, Weller M, von Deimling A (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694. https://doi.org/10.1016/S1470-2045(17)30155-9 CrossRefPubMed

39.

Jiao Y, Feng Y, Wang X (2018) Regulation of tumor suppressor gene CDKN2A and encoded p16-INK4a protein by covalent modifications. Biochemistry (Mosc) 83:1289–1298. https://doi.org/10.1134/S0006297918110019 CrossRef

Title: Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma
Authors: Anne Guyot
Mathilde Duchesne
Sandrine Robert
Anne-Sophie Lia
Paco Derouault
Erwan Scaon
Leslie Lemnos
Henri Salle
Karine Durand
François Labrousse
Publication date: 01-12-2019
Publisher: Springer US
Keywords: Meningioma
Meningioma
Published in: Journal of Neuro-Oncology / Issue 3/2019
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-019-03333-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2019

Correction to: White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab

Increased 14C-acetate accumulation in IDH-mutated human glioblastoma: implications for detecting IDH-mutated glioblastoma with 11C-acetate PET imaging

EGFR gene amplification in monocentric and multicentric glioblastoma

Evaluating pediatric spinal low-grade gliomas: a 30-year retrospective analysis

Radiation chronotherapy—clinical impact of treatment time-of-day: a systematic review

Surgical and radiosurgical treatment strategies for Cushing’s disease