CDKN2A deletion in pediatric versus adult glioblastomas and predictive value of p16 immunohistochemistry

Abstract

Cell cycle regulator genes are major target of mutation in many human malignancies including glioblastomas (GBMs). CDKN2A is one such tumor suppressor gene which encodes p16INK4a protein and serves as an inhibitor of cell cycle progression. Very few studies are available regarding the association of CDKN2A deletion with p16 protein expression in GBMs. There is limited data on the frequency of CDKN2A deletion in different age groups. The aim of the present study was to analyze the frequency of CDKN2A gene deletions in GBM and correlate CDKN2A deletional status with (i) age of the patient (ii) p16 protein expression and (iii) other genetic alterations, namely EGFR amplification and TP53 mutation. A combined retrospective and prospective study was conducted. Sixty seven cases were included. The patients were grouped into pediatric (≤ 18 years), young adults (19-40 years) and older adults (>40 years). CDKN2A and EGFR status were assessed by Fluorescence in situ Hybridization.TP53 mutation was analyzed by PCR based method. p16 expression was assessed using immunohistochemistry. CDKN2A deletion was noted in 40.3% cases of GBM with majority being homozygous deletion (74%). It was commoner in primary GBMs (65.8%) and cases with EGFR amplification (50%). A variable frequency of CDKN2A was observed in older adults (42.3%), young adults (44%), and pediatric patients (31.25%). The difference however was not statistically significant. There was statistically significant association between CDKN2A deletion and p16 immunonegativity with a high negative predictive value of immunohistochemistry.

Practical Molecular Pathologic Diagnosis of Infiltrating Gliomas

“…IHC to assess loss of p16 expression can be used with high positive predictive value for homozygous CDKN2A deletion. 93,98 Negative p16 IHC can be seen in other conditions, however, such as promoter methylation, and is not specific to CDKN2A deletion. Additionally, it can be difficult to interpret due to intermixed non-neoplastic cells.…”

“…24,82,93 Rates for pediatric high-grade gliomas vary between 31% and 52%. 62,93 The frequency of CDKN2A loss in low-grade infiltrating gliomas are significantly lower in the literature ranging from no loss in grade II astrocytomas to 10% to 13% loss in both astrocytomas and oligodendrogliomas. 24,84,91 CDKN2A/p16 deletion is not helpful in distinguishing pilocytic astrocytomas and pleomorphic xanthoastrocytomas from infiltrating gliomas because anaplastic subsets of the former 2 also harbor deletions.…”

“…CDKN2A deletion is seen in 30% to 68% of adult glioblastomas and 25% to 63% of anaplastic gliomas. 24,76,82,[90][91][92][93][94] It is more frequent in de novo glioblastomas and recurrent gliomas compared with secondary glioblastomas and primary gliomas, respectively. 24,82,93 Rates for pediatric high-grade gliomas vary between 31% and 52%.…”

“…24,76,82,[90][91][92][93][94] It is more frequent in de novo glioblastomas and recurrent gliomas compared with secondary glioblastomas and primary gliomas, respectively. 24,82,93 Rates for pediatric high-grade gliomas vary between 31% and 52%. 62,93 The frequency of CDKN2A loss in low-grade infiltrating gliomas are significantly lower in the literature ranging from no loss in grade II astrocytomas to 10% to 13% loss in both astrocytomas and oligodendrogliomas.…”

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

“…Furthermore, compared with serum cultured glioma cell lines they have been shown on both histological and genetic levels to serve as a better model of human gliomas when injected into the brains of mice [75–78]. Figure 5 shows the results of cytotoxicity evaluation for compound 5 against GBM neurosphere cultures carrying a tumor suppressor cdkn2a deletion [79] as well as PDGFB [80] and EGFRvIII [81] and amplifications, representing frequent mutations in high-grade astrocytic tumors. The data indicate that compound 5 used at 20 μM (average GI 50 in Table 1) shows effectiveness similar to that of cannabidiol (CBD) at 10 μM, an orphan drug advanced to phase II clinical trials for the treatment of GBM.…”