Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Brain Tumor Pathology
Published in: Brain Tumor Pathology 2/2023

14-02-2023 | Astrocytoma | Original Article

Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma

Authors: Yuzaburo Shimizu, Mario Suzuki, Osamu Akiyama, Ikuko Ogino, Yuko Matsushita, Kaishi Satomi, Shunsuke Yanagisawa, Makoto Ohno, Masamichi Takahashi, Yasuji Miyakita, Yoshitaka Narita, Koichi Ichimura, Akihide Kondo

Published in: Brain Tumor Pathology | Issue 2/2023

Login to get access

Abstract

The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2A/B homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPA/CytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5.
Appendix
Available only for authorised users
Literature
1.
Louis DN (2016) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon.
2.
Brat DJ, Aldape K, Colman H et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603–608CrossRefPubMedPubMedCentral
3.
4.
Appay R, Dehais C, Maurage CA et al (2019) CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol 21:1519–1528CrossRefPubMedPubMedCentral
5.
Yang RR, Shi ZF, Zhang ZY 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 30:541–553CrossRefPubMed
6.
Shirahata M, Ono T, Stichel D et al (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:153–166CrossRefPubMed
7.
Passon N, Pozzo F, Molinis C et al (2009) A simple multiplex real-time PCR methodology for the SMN1 gene copy number quantification. Genet Test Mol Biomarkers 13:37–42CrossRefPubMed
8.
Zhang X, Huang M, Wu X et al (2013) GSTM1 copy number and promoter haplotype as predictors for risk of recurrence and/or second primary tumor in patients with head and neck cancer. Pharmgenomics Pers Med 6:9–17PubMedPubMedCentral
9.
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 34:688–700CrossRefPubMed
10.
Arita H, Narita Y, Matsushita Y et al (2015) Development of a robust and sensitive pyrosequencing assay for the detection of IDH1/2 mutations in gliomas. Brain Tumor Pathol 32:22–30CrossRefPubMed
11.
Luchman HA, Stechishin OD, Dang NH et al (2012) An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro Oncol 14:184–191CrossRefPubMed
12.
Setoodeh R, Schwartz S, Papenhausen P et al (2013) Double-hit mantle cell lymphoma with MYC gene rearrangement or amplification: a report of four cases and review of the literature. Int J Clin Exp Pathol 6:155–167PubMedPubMedCentral
13.
14.
Kamb A, Gruis NA, Weaver-Feldhaus J et al (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440CrossRefPubMed
15.
Suzuki H, Aoki K, Chiba K et al (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47:458–468CrossRefPubMed
16.
Reis GF, Pekmezci M, Hansen HM et al (2015) CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J Neuropathol Exp Neurol 74:442–452CrossRefPubMed
17.
Korshunov A, Casalini B, Chavez L et al (2019) Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol Appl Neurobiol 45:108–118CrossRefPubMed
18.
Aoki K, Nakamura H, Suzuki H et al (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20:66–77CrossRefPubMed
19.
Varn FS, Johnson KC, Martinek J et al (2022) Glioma progression is shaped by genetic evolution and microenvironment interactions. Cell 185:2184-2199.e16CrossRefPubMed
20.
Kocakavuk E, Anderson KJ, Varn FS et al (2021) Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet 53:1088–1096CrossRefPubMedPubMedCentral
21.
22.
Schmidt EE, Ichimura K, Reifenberger G, Collins VP (1994) CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54:6321–6324PubMed
23.
Schmidt EE, Ichimura K, Messerle KR et al (1997) Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours. Br J Cancer 75:2–8CrossRefPubMedPubMedCentral
Metadata
Title
Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma
Authors
Yuzaburo Shimizu
Mario Suzuki
Osamu Akiyama
Ikuko Ogino
Yuko Matsushita
Kaishi Satomi
Shunsuke Yanagisawa
Makoto Ohno
Masamichi Takahashi
Yasuji Miyakita
Yoshitaka Narita
Koichi Ichimura
Akihide Kondo
Publication date
14-02-2023
Publisher
Springer Nature Singapore
Published in
Brain Tumor Pathology / Issue 2/2023
Print ISSN: 1433-7398
Electronic ISSN: 1861-387X
DOI
https://doi.org/10.1007/s10014-023-00450-z

Other articles of this Issue 2/2023

Brain Tumor Pathology 2/2023 Go to the issue

Review Article

Clinical characteristics and radiological features of glioblastoma, IDH-wildtype, grade 4 with histologically lower-grade gliomas

Original Article

Spatial metabolic heterogeneity of oligodendrogliomas at single-cell resolution

Original Article

Clinical, histopathological and molecular risk factors for recurrence of pilocytic astrocytomas: brainstem/spinal location, nestin expression and gain of 7q and 19 are associated with early tumor recurrence

Original Article

Impact of tumor markers on diagnosis, treatment and prognosis in CNS germ cell tumors: correlations with clinical practice and histopathology

Review Article

An enduring debate on gliomatosis cerebri

Preface

Preface for Brain Tumor Pathology vol.40 issue 2