Top

Published in:

24-01-2024 | Astrocytoma | Case Study

CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization

Authors: Manali Ranade, Sridhar Epari, Omshree Shetty, Sandeep Dhanavade, Sheetal Chavan, Ayushi Sahay, Arpita Sahu, Prakash Shetty, Aliasgar Moiyadi, Vikash Singh, Archya Dasgupta, Abhishek Chatterjee, Sadhana Kannan, Tejpal Gupta

Published in: Journal of Neuro-Oncology | Issue 1/2024

Abstract

Introduction

CDKN2A/B homozygous deletion is one of the defining features of grade 4 in IDH-mutant astrocytic tumours.

Aim

To evaluate CDKN2A/B-deletion in IDH-mutant astrocytic tumours and its clinicopathological impact.

Materials and methods

CDKN2A/B-deletion was evaluated by Fluorescence in-situ hybridisation (FISH) and interpreted by two recently accepted methods.

Results

Eighty-three out of 94 cases (histologically—grade 2: 3, grade 3: 46, grade 4: 34) were interpretable on FISH. Concordant CDKN2A/B-deletion was observed in 71% (27/38) of lower-grade tumours (n = 49) and 90% (27/30) of histological grade 4 tumours (n = 34). Both the interpretation methods showed good agreement (Kappa = 0.75).

CDKN2A/B-deletion showed an inverse correlation for < 10% MIB-1 labeling index (p = 0.01) while that by method-2 showed a significant correlation for grade 4 (p = 0.02). No significant correlation was observed for any other clinicopathological parameters.

Twenty-four patients showed progression/recurrence (including deaths), and no significant difference in frequency of CDKN2A/B deletion was observed among cases with disease progression across different histological grades.

Conclusions

CDKN2A/B-deletion was observed across all the histological grades of IDH-mutant astrocytic tumours, expectedly more in the higher grade. FISH, as a method, can be used for the detection of CDKN2A/B homozygous deletion, when there is concordant interpretation.

Lim S, Kaldis P (2013) Cdks, cyclins and CKIs: Roles beyond cell cycle regulation. Development 140:3079–3093. https://doi.org/10.1242/dev.091744CrossRefPubMed

Rao L, Miller D, Newcomb E (1997) Correlative immunohistochemistry and molecular genetic study of the inactivation of the p16INK4A genes in astrocytomas. Diagn Mol Pathol 6:115–122. https://doi.org/10.1097/00019606-199704000-00008CrossRefPubMed

Louis D, Perry A, Wesseling P et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106CrossRefPubMedPubMedCentral

Brat D, Aldape K, Colman H et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603–608. https://doi.org/10.1007/s00401-020-02127-9CrossRefPubMedPubMedCentral

Park S, Won J, Kim S et al (2017) Molecular testing of brain tumor. J Pathol Transl Med 51:205–223. https://doi.org/10.4132/jptm.2017.03.08CrossRefPubMedPubMedCentral

Ambros P, Ambros I; SIOP Europe Neuroblastoma Pathology, Biology, and Bone Marrow Group (2001) Pathology and biology guidelines for resectable and unresectable neuroblastic tumors and bone marrow examination guidelines. Med Pediatr Oncol 37:492–504. https://doi.org/10.1002/mpo.1242CrossRef

Marker D, Pearce T (2020) Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-mutant astrocytomas. Acta Neuropathol Commun 8:1–12. https://doi.org/10.1186/s40478-020-01044-yCrossRef

Hsieh C, Su I, Huang C et al (2016) The prognostic value of O6-methylguanine-DNA methyltransferase gene promoter methylation detected by gel-based methylation-specific polymerase chain reaction in patients with glioblastoma multiforme: A systematic review. Int J Clin Exp Med 9:10899–10906

Reis G, Pekmezci M, Hansen H et al (2016) CDKN2A Loss Is Associated with Shortened Overall Survival in Lower Grade (World Health Organization II-III) Astrocytomas. J Neuropathol Exp Neurol 5:1–8. https://doi.org/10.1097/NEN.0000000000000188CrossRef

10.

Appay R, Dehais C, Maurage C et al (2019) CDKN2A Homozygous Deletion Is a Strong Adverse Prognosis Factor in Diffuse Malignant IDH-mutant Gliomas. Neuro Oncol 21:1519–1528. https://doi.org/10.1093/neuonc/noz124CrossRefPubMedPubMedCentral

11.

Yang R, Shi Z, Zhang Z et al (2020) IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations. Brain Pathol 30:541–553. https://doi.org/10.1111/bpa.12801CrossRefPubMed

12.

Lu V, O’Connor K, Shah A et al (2020) The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature. J Neurooncol 48:221–229. https://doi.org/10.1007/s11060-020-03528-2CrossRef

13.

Shirahata M, Ono T, Stichel D et al (2018) Novel, improved grading system(S) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:153–166. https://doi.org/10.1007/s00401-018-1849-4CrossRefPubMed

14.

Perry A, Nobori T, Ru N et al (1997) Detection of p16 gene deletions in gliomas: a comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR. J Neuropathol Exp Neurol 56:999–1008. https://doi.org/10.1097/00005072-199709000-00005CrossRefPubMed

15.

Satomi K, Ohno M, Matsushita Y et al (2021) Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2A homozygous deletion in the assessment of adult-type infiltrating astrocytoma. Mod Pathol 34:688–700. https://doi.org/10.1038/s41379-020-00701-wCrossRefPubMed

16.

Park J, Kang J, Lim K et al (2021) The prognostic significance of p16 expression pattern in diffuse gliomas. J Pathol Transl Med 55:102–111. https://doi.org/10.4132/jptm.2020.10.22CrossRefPubMed

17.

Geyer L, Wolf T, Chenard M et al (2023) p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances. Cancers 15:1–12. https://doi.org/10.3390/cancers15051512CrossRef

18.

Suman S, Sharma R, Katiyar V et al (2022) Role of CDKN2A deletion in grade 2/3 IDH-mutant astrocytomas: need for selective approach in resource-constrained settings. Neurosurg Focus 53:1–9. https://doi.org/10.3171/2022.9.FOCUS22427CrossRef

19.

Korshunov A, Casalini B, Chavez L et al (2019) Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol Appl Neurobiol 45:108–118. https://doi.org/10.1111/nan.12523CrossRefPubMed

20.

Purkait S, Jha P, Sharma M et al (2013) CDKN2A deletion in pediatric versus adult glioblastomas and predictive value of p16 immunohistochemistry. Neuropathology 33:405–412. https://doi.org/10.1111/neup.12014CrossRefPubMed

21.

Burns K, Ueki K, Jhung S et al (1998) Molecular Genetic Correlates of p16, cdk4 andpRb Immunohistochemistry in Glioblastomas. J Neuropathol Exp Neurol 57:122–130. https://doi.org/10.1097/00005072-199802000-00003CrossRefPubMed

22.

Vij M, Cho B, Yokoda R et al (2023) P16 immunohistochemistry is a sensitive and specific surrogate marker for CDKN2A homozygous deletion in gliomas. Acta Neuropathol Commun 11:1–9. https://doi.org/10.1186/s40478-023-01573-2CrossRef

23.

Maragkou T, Reinhard S, Jungo P et al (2023) Evaluation of MTAP and p16 immunohistochemical deficiency as surrogate marker for CDKN2A/B homozygous deletion in gliomas. Pathology 55:466–477. https://doi.org/10.1016/j.pathol.2023.01.005CrossRefPubMed

Title: CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization
Authors: Manali Ranade
Sridhar Epari
Omshree Shetty
Sandeep Dhanavade
Sheetal Chavan
Ayushi Sahay
Arpita Sahu
Prakash Shetty
Aliasgar Moiyadi
Vikash Singh
Archya Dasgupta
Abhishek Chatterjee
Sadhana Kannan
Tejpal Gupta
Publication date: 24-01-2024
Publisher: Springer US
Keywords: Astrocytoma
Astrocytoma
Astrocytoma
Published in: Journal of Neuro-Oncology / Issue 1/2024
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-024-04569-7

At a glance: The STEP trials

Springer Medicine

CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization

Abstract

Introduction

Aim

Materials and methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Aim

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

Midline invasion predicts poor prognosis in diffuse hemispheric glioma, H3 G34-mutant: an individual participant data review

Correction to: Intrathecal chemotherapy for leptomeningeal disease in high-grade gliomas: a systematic review

Correction to: The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review

Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma

Imaging predictors of 4q12 amplified and RB1 mutated glioblastoma IDH-wildtype

Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery