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Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing

Acta Neuropathologica Communications volume 12, Article number: 180 (2024) Cite this article

Abstract

CDKN2A/B deletions are prognostically relevant in low- and high-grade gliomas. Data on this is derived from heterogeneous series, an accurate estimation of survival risk from homozygous CDKN2A/B deletion is missing. Besides genetic testing, p16-immunohistochemistry (IHC) as a less cost intensive means for indirect detection of CDKN2A/B alterations is possible but not validated in larger datasets. The present meta-analysis aimed to (1) reconstruct individual patient data (IPD) and estimate overall survival (OS) stratified by CDKN2A/B status from all literature and to (2) determine accuracy of p16 testing for CDKNA2/B detection from published studies. For survival analysis according to CDKN2A/B status 460 records were screened, four articles with 714 participants were included. In IDH-wildtype (IDH-wt) gliomas, 57.07% harbored the deletion compared to 9.76% in IDH-mutant (IDH-mut) gliomas. Median OS of patients with IDH-wt gliomas and homozygous CDKN2A/B deletion was 13.0 months compared to 18.0 months with non-deleted CDKN2A/B (p = 0.014, Log-Rank). With homozygous deletion of CDKN2A/B the risk of death was increased by 1.5 (95%-CI 1.1–2.1). Median OS in patients with IDH-mut gliomas without CDKN2A/B deletion was 92.0 months compared to 40.0 months with CDKN2A/B deletion (p < 0.001, Log-Rank). CDKN2A/B deletions were associated with a significantly shorter OS (HR = 3.2; 95%-CI 2.2–5.5). For p16 IHC analysis, 10 eligible studies with 1087 examined samples were included. The cut-off for retention differed between the studies. In 588/662 p16 retained cases CDKN2A/B deletions was not detected, implying a negative predictive value (NPV) of p16 staining of 88.8%. Conversely, 279/425 p16 absent cases showed a CDKN2A/B deletion resulting in a positive predictive value (PPV) of 65.6%. Sensitivity of p16 staining for CDKN2A/B detection was 79.0%, specificity 80.1%. Highest diagnostic accuracy of p16 IHC was reached with a cut-off of > 5% and within IDH-mut glioma.

Introduction

Malignant gliomas are the most frequent primary intracerebral neoplasms in adults [25]. Prognosis worsens with increasing World Health Organization (WHO) Grade from > 5–10 years in Grade 2 gliomas to 1–2 years in Grade 4 gliomas [21]. Within the last decade, the WHO grading system of gliomas that is historically based upon histopathologic markers of malignancy has been significantly altered and augmented by use of molecular alterations like isocitrate dehydrogenase (IDH)-1/2-mutation [5]. Genetically, the presence of IDH1/2-mutations defines a distinct class of diffuse adult glioma with overall improved prognosis as IDH-wt glioma [14]. Among IDH-mut gliomas the presence of homozygous cyclin-dependent kinase inhibitor 2 A/B (CDKN2A/B) gene deletions of the chromosome 9p21 are associated with significantly poorer prognosis [1, 2, 19, 32, 35, 40]. Due to this, homozygous CDKN2A/B deleted IDH-mut astrocytomas are classified as WHO grade 4 [39]. Data on the impact of CDKN2A/B on prognosis is derived from heterogenous series and accurate estimation of prognosis in case of CDKN2A/B deletion is difficult. Given the increasing relevance of CDKN2A/B deletions, reliable and cost-effective means of detections are needed. Besides genetic testing, indirect immunohistochemical testing for p16 is feasible but little defined in its accuracy [4, 44].

The present meta-analysis had two aims: (1) to investigate the clinical prevalence of CDKN2A/B deletions and the impact of CDKN2A/B deletions on OS in all reported series of malignant gliomas and (2) to precisely assess the test accuracy of p16 immunohistochemistry (IHC) for indirect CDKN2A/B detection from all reported series so far.

Methods and materials

Search strategy and study inclusion

To obtain eligible studies three databases (Cochrane library, PubMed and Web of Science) were screened up to September 27, 2023. The databases were screened, and English publications were retrieved by using the following MeSH terms: (1) „CDKN2A“ AND „glioma“; (2) „CDKN2B“ AND „glioma“; (3) „CDKN2A/B“ AND „glioma“. To be included in the meta-analysis studies must provide CDKN2A/B status and IDH status as well as OS data shown by Kaplan-Meier plots with corresponding number at risk tables. Studies without number at risk tables were excluded due to impossibility of reconstructing IPD.

Suitable studies for investigating the CDKN2A/B and p16 concordance were explored by using the MeSH terms: (1) “p16” AND “CDKN2A” AND “glioma”; (2) “p16” AND “CDKN2B” AND “glioma” and (3) “p16” AND “CDKN2A/B” AND “glioma”. For inclusion, studies had to report the association between p16 staining and CDKN2A/B status. Covidence was used to accelerate the systematic review process by importing all references from the databases. The website provides an automatic duplication detection to eliminate redundant records. Then titles, abstracts and full text were successively screened manually to extract suitable studies.

Data extraction

Clinical and neuropathological characteristics (e.g. age, performance status, glioma type, IDH1-mutation status, MGMT status) were summarized. The extraction of IPD required Kaplan-Meier plots with given number at risk tables to use the application DigitizeIt (Bormann, Version 2.5.10 on MacOS, Braunschweig, Germany). No study provides the IPD in the results or supplementary material. To gather IPD, images of the Kaplan-Meier plots are imported in DigitizeIt. By establishing the coordinate system and pinpointing data points on the graph, the system creates record of x- and y-values that can be exported as a CSV file. After extraction, the digitized data were used to reconstruct the Kaplan-Meier curves using the web application IPDfromKM (Liu et al., Version 1.2.3.0, Houston, USA) to finally obtain IPD [20].

Statistical analysis

The reconstructed IPD of all included studies were summarized for further analysis. New Kaplan-Meier plots of the pooled data were created by the R package Survminer with R (Version 4.3.1, Vienna, Austria). Median OS rates were constructed and Log-rank tests as well as the hazard ratios via cox regression were performed in SPSS (IBM, Version 29.0.1.1 on Windows 10). For survival analysis CDKN2A/B status and IDH status were regarded.

Results

Study characteristics

The CDKN2A/B status and OS depicted as a Kaplan-Meier plot was provided in four eligible studies for 714 patients (Fig. 1). The included studies are authored by Draaisma et al. [9], Guo et al. [12], Hsu et al. [17] and Tesileanu et al. [40].

The results of Draaisma et al. [9] (EORTC 26091 TAVAREC Trial, phase II) and Tesileanu et al. [40] (EORTC CATNON-Trial, phase III) were generated in post-hoc analyses from randomized, multicenter studies including patients from Europe, Australia and North America. The EORTC CATNON trial primarily examined the effect of adding temozolomide (TMZ), either concurrently with radiotherapy, as adjuvant and both current and adjuvant treatment to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic glioma [42]. Within the TAVAREC trial the use of bevacizumab (BEV) in patients with first recurrence of grade 2 or 3 gliomas who did not have 1p/19q co-deletion was assessed regarding OS [43].

The data of Guo et al. [12] and Hsu et al. [17] were compiled within monocentric retrospective analysis designed primarily for detection of influence of molecular alterations on prognosis of malignant gliomas.

Fig. 1
figure 1

PRISMA flow diagram for study selection

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Patient characteristics

Examined tumor types differed between studies. While Hsu et al. [17] only investigated IDH-wt glioblastoma (GBM), Guo et al. [12] included histologic IDH-wt GBM and molecular IDH-wt GBM (histologic astrocytoma). In both studies next generation sequencing (NGS) was used to determine CDKN2A/B status. Hsu et al. [17] provided OS data on CDKN2A and CDKN2B separately. It was specified in the manuscript of Hsu et al. [17] that all patients harboring a CDKN2B deletion (n = 75) were also CDKN2A deleted, so the OS data of CDKN2A deleted patients (n = 89) were used for further investigation in the meta-analysis. Tesileanu et al. [40] analyzed patients with IDH-mut anaplastic astrocytoma for influence of CDKN2A/B deletion. Draaisma et al. [9] reported CDKN2A/B results on a mixed population of WHO Grade 2–4 gliomas: astrocytoma (68.6%), GBM (14.8%, not included in meta-analysis), oligodendroglioma (ODG, 2.5%, not included in meta-analysis), the histological status of the remaining samples (13.9%) was inconclusive. Both used DNA methylation profiling to examine CDKN2A/B status.

In the studies dealing with IDH-mut gliomas median patient age was lower (Tesileanu et al. [40]: 41y, range: 18–82; Draaisma et al. [9]: 43y, range: 34–52) compared to the studies of Guo et al. [12] (55.5y, range: 40.3–70.2) and Hsu et al. [17] (63y, 24.8–85.1) on IDH-wt GBM. Overall, more male than female patients were included (58.6% male, 41.4% female). In the study of Guo et al. [12] gender was nearly balanced (male: 52.4%) while Tesileanu et al. [40] (male 58.6%), Hsu et al. [17] (male: 60.5%) and Draaisma et al. [9] (65.6%) showed a male predominance.

Regarding follow-up data in Guo et al. [12] a median follow-up time of 11.5 months is given. The EORTC CATNON trial provides a median follow-up of 27.0 months and the TAVAREC trial a median follow-up time of 28.0 months [42, 43].

MGMT status was described in different extents in all studies. Most gliomas were MGMT-promoter methylated in Tesileanu et al. [40] (68.0%) and Draaisma et al. [9] (73.0%). In Hsu et al. [17] the MGMT status is only given for a minority of patients (methylated: 25.1%, unmethylated 7.2%), Guo et al. [12] reported methylation for 35.9% of patients as methylated.

More detailed patient characteristics are displayed in Supplementary Table 1 in Additional file 1.

Characteristics of tumor treatment

IDH -wt gliomas

Hsu et al. [17] state the resection status as positive (67.7%) or negative (32.3%). Guo et al. [12] describe the resection status as total resection (61.8%), subtotal resection (17.8%) and biopsy (20.4%).

Information on adjuvant therapy schemes is provided in Hsu et al. [17], where all (167) patients received RT of the tumor cavity (mostly 60 Gy in 30 fractions) as well as concomitant and adjuvant TMZ treatment. Likewise, postoperative treatment in Guo et al. [12] comprised the combination of RT and TMZ (75/117, 64.1%) according to the Stupp-Protocol.

IDH -mut gliomas

In Tesileanu et al. [40] the percentage of biopsies (15.5%) and resections (84.5%) is given but not further specified concerning total or subtotal resection. Draaisma et al. [9] did not report initial tumor resection status.

For postoperative treatment in the CATNON cohort of Tesileanu et al. [40] patients were equally randomized to receive RT alone (33 fractions of 1.8 Gy), RT with concurrent TMZ (75mg/m2 daily for 7 weeks), RT with adjuvant TMZ (150-200mg/m2 on day 1–5 in 12 four-week-cycles) or RT with concurrent and adjuvant TMZ. In Draaisma et al. [9] almost all patients received initial RT (97.5%) while some patients underwent prior chemotherapy containing PCV (2, 1.6%) or TMZ (26, 21.3%). At recurrence, all patients (122) were randomized and received either chemotherapy containing TMZ (61, 50%) or TMZ and BEV (61, 50%). All other studies do not report treatment types at recurrence.

More detailed treatment characteristics are displayed in Supplementary Table 1 in Additional file 1.

Frequency of CDKN2A/B deletion

Overall, in all studies the frequency of homozygous CDKN2A/B deletion was 23.8% (170/714). There was a clear difference in prevalence of CDKN2A/B abnormality dependent on IDH-mutation status. In IDH-wt gliomas, more than half of the tumors (57.1%) harbored the deletion in contrast to only 9.8% of IDH-mut gliomas.

In all chosen studies homozygous deletion of CDKN2A/B was analyzed. OS data for hemizygous deletions was not available. In Hsu et al. [17] the median OS for CDKN2A deletion was 13.2 months and for CDKN2B deletion 12.8 months. In Guo et al. [12] CDKN2A/B was summarized and the median OS was 12.3 months. A higher median OS is depicted in Tesileanu et al. [40] with 36.6 months. In Draaisma et al. [9] the primary IDH-mut gliomas showed a median OS of 36.6 months.

Survival analysis of individual patient data

IDH -wt gliomas

Median survival of patients with IDH-wt glioma and homozygous CDKN2A/B deletion was 13.0 months (95%-CI 11.2–14.8). In contrast, median survival of IDH-wt GBM with non-deleted CDKN2A/B was 18.0 months (95%-CI 16.2–19.8); χ²(1) = 6.086, p = 0.014, Log-Rank. Therefore, a homozygous deletion of CDKN2A/B in glioma patients with IDH-wt increased risk of death, HR = 1.6 (95%-CI 1.1–2.1), Fig. 2. In the IDH-wt cohort the 1-year OS rate without CDKN2A/B deletion was 55%, with homozygous deletion it was 36%. After two years the OS was 32% and 17% respectively. Detailed OS rates from 6 to 60 months are fully displayed in Table 1.

IDH -mut gliomas

Median overall survival time in patients with IDH-mut glioma without CDKN2A/B deletion was 92.0 months (95%-CI 76.6–107.4) compared to 40.0 months with CDKN2A/B deletion (95%-CI 30.4–49.6); χ²(1) = 42.8; p < 0.001, Log-Rank. A CDKN2A/B deletion was associated with a significantly shorter overall survival time (HR = 3.2; 95%-CI 2.2–4.5), Fig. 3. The 1-year OS in the IDH-mut cohort was 97% and 88% respectively. After two years 92%/73% survived.

Detailed OS rates from 6 to 60 months are fully displayed in Table 1.

Likewise, OS differed greatly depending on IDH-mutation status. In all patients regardless of CDKN2A/B status the median OS time in patients with IDH-wt was 15.0 months (95%-CI 12.19–17.81). In contrast the median OS time with IDH-mutation was 87.0 months (95%-CI 77.16–96.84); χ²(1) = 29.56; p < 0.001, Log-Rank.

Detailed OS rates from 6 to 60 months are fully displayed in Table 1.

Table 1 Overall survival rates at several time points depending on CDKN2A/B status in IDH-wt and IDH-mut glioma
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Fig. 2
figure 2

Kaplan-Meier chart of IDH-wt glioma displaying overall survival probability stratified by non-deleted CDKN2A/B (green) and CDKN2A/B deletion (orange)

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Fig. 3
figure 3

Kaplan-Meier chart of IDH-mut glioma displaying overall survival probability stratified by non-deleted CDKN2A/B (teal) and CDKN2A/B deletion (orange)

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Predictive value of p16 IHC staining

In 10 eligible studies a total of 1087 samples were examined. In all studies IHC was used to determine p16 status. The cut-off for retention differed between the studies. Bortolotto et al. [4], Geyer et al. [11], Rao et al. [31] and Vij et al. [44] classified samples p16 retained when at least 5% of the cells showed IHC staining while Park et al. [27], Purkait et al. [29] set a cut-off of 1%. In Maragkou et al. [23], Purkait et al. [30] and Suman et al. [38] a complete absence of staining was classified as p16 loss. Burns et al. [6] did not give further explanation how specimens were classified as retained or absent but stated that four slides were stained as confirmation of the result. Information on details of cell count is missing in some studies. Bortolotto et al. [4] scanned 10 high-power fields at 400x magnification in each tumor section. Comparably Vij et al. [44] used the average of the minimum and maximum percentage of tumor cell staining in an area of highest tumor agglomeration at 10x magnification. An amount of 1000 cells were counted in Purkait et al. [29] as well in areas of strongest nuclear staining requiring at least 10 representative microscopic fields at 400x magnification. To determine CDKN2A/B status a Multiplex PCR was performed in Bortolotto et al. [4], Burns et al. [6] and Rao et al. [31]. Vij et al. [44] performed NGS. In all other studies fluorescence in situ hybridization (FISH) was used to define the CDKN2A/B status. In Geyer et al. [11] and Purkait et al. [31] the CDKN2A/B deletion status as hemi- or homozygous was stated separately (Geyer et al. [11]: 15 hetero-, 38 homozygous; Purkait et al. [31]: 7 hemi-, 20 homozygous, Maragkou et al. [23]: 18 hemi-, 33 homozygous). Geyer et al. [11] did not include the hemizygous samples in the results. In the following analysis a hemizygous deletion of CDKN2A/B was treated as a homozygous deletion.

Patient characteristics of and how p16 IHC was evaluated in the included studies are summarized in Supplementary Tables 2 and 3 in Additional file 1.

P16 immunohistochemistry as surrogate marker for homozygous CDKN2A/B deletions

Of all pooled samples in 734/1087 (68%) cases the CDKN2A/B gene was not deleted. Conversely, 353/1087 (32%) showed CDKN2A/B deletions. A total of 662/1087 samples (61%) were classified as p16 retained and 425/1087 (40%) were determined as p16 absent (Table 2). The correlation of CDKN2A/B status and p16 staining can be summarized as following: In 588/662 p16 retained cases CDKN2A/B deletion was not detected, implying a NPV of p16 staining of 88.8%. Conversely, 279/425 p16 absent cases showed a CDKN2A/B deletion resulting in a PPV of 65.6%. With these total numbers the accuracy of a p16 staining to predict the CDKN2A/B status can be calculated. The cumulative data of the studies show that in 279/353 cases the p16 staining correctly identified the deletion of CDKN2A/B meaning its sensitivity results in 79.0%. The specificity of absent p16 staining to identify 588/734 samples with non-deletion of CDKN2A/B is 80.1%.

Table 2 Crosstab of association of p16 and CDKN2A/B status of all pooled samples
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After pooling of respective samples different cut-offs for p16 IHC retention impacted diagnostic accuracy (Table 3, Supp. Tables 4–6).

Concerning sensitivity, the 5% cut-off (89.6% ± 5.8%) showed a higher diagnostic accuracy when compared to both the 1% cut-off (71.2% ± 7.1%) and complete absence as cut-off (77.2% ± 9.2%). For specificity, the 5% cut-off (91.3% ± 3.7%) scored highest compared to both the 1% cut-off (71.7% ± 5.7%) and complete absence as cut-off (80.0% ± 4.9%). Regarding PPV, using a 5% cut-off achieved 82.6% ± 6.9%, higher than the 1% cut-off (62.4% ± 7.1%) and complete absence as cut-off (54.5% ± 9.2%). For NPV, a difference was noted between the 5% cut-off (95.0% ± 2.9%) and the 1% cut-off (79.1% ± 5.4%), as well as between the 1% cut-off and complete absence as cut-off (91.9% ± 3.6%).

Table 3 Comparison of diagnostic accuracy of metrics of different cut-offs for p16 IHC retention
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Almost all data could be separated between IDH-mut astrocytoma, IDH-wt GBM and IDH-mut 1p/19q codeleted ODG regarding their p16 IHC testing and CDKN2A/B status. Geyer et al. [11] presented p16 IHC data for every glioma subtype but did not show the CDKN2A/B status for the samples separately. Park et al. [27] did not specify p16 status for CDKN2A/B status of glioma subtypes. The diagnostic accuracy of p16 IHC testing varied between IDH-mut and IDH-wt glioma (Table 4, Supp. Tables 7–10). Sensitivity between IDH-mut glioma (82.0% ± 11.6%) and IDH-wt GBM (80.8% ± 7.0%) was comparable high. The p16 IHC testing in IDH-mut glioma showed a specificity of 85.3% ± 4.2%, which appeared higher than in IDH-wt GBM (68.3% ± 9.1%). Similarly, NPV in IDH-mut glioma outperformed results in IDH-wt GBM (96.3% ± 2.4% vs. 74.2% ± 8.9%).

When comparing different glioma subtypes differences in diagnostic accuracy were again noted. Sensitivity in IDH-mut 1p/19q codeleted ODG (87.5% ± 16.2%) outperformed IDH-wt GBM (80.8% ± 6.9%) and IDH-mut astrocytoma (79.4% ± 13.6%).

Specificity was lowest in IDH-wt GBM (68.3% ± 9.1%) compared to IDH-mut astrocytoma (85.2% ± 4.6%) and IDH-mut 1p/19q codeleted ODG (86.0% ± 10.4%). PPV in IDH-wt GBM (75.9% ± 7.3%) was higher than in IDH-mut astrocytoma (44.3% ± 12.5%) and comparable to IDH-mut 1p/19q codeleted ODG (70.0% ± 20.1%). NPV was lower for IDH-wt GBM (74.2% ± 8.9%) when compared to both IDH-mut 1p/19q codeleted ODG (94.9% ± 6.9%) and IDH-mut astrocytoma (96.5% ± 2.5%).

Table 4 Comparison of p16 IHC retention in different glioma subtypes
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Associations between p16 IHC status and patient survival

Survival analysis regarding p16 IHC status only is mostly not provided in the selected studies. Park et al. [27] demonstrated significant difference in cumulative survival depending on p16 loss in the whole glioma cohort (p < 0.001) and in a Multivariate Cox regression analysis p16 IHC loss was significantly associated with worse survival in IDH-mut gliomas (HR = 2.6, 95%-CI 1.3–5.4, p = 0.008). Geyer et al. [11] presented significant difference in cumulative survival of IDH-wt GBM (p < 0.001) and grade 3 ODG (p < 0.001). Interestingly, the CDKN2A status in p16 absent samples showed no significant difference between non-deleted and homozygous deleted samples in the whole glioma cohort (p = 0.97). Suman et al. [38] reported worse 3-year OS (p16 absent 54% vs. 76% p16 retained (p = 0.039) and PFS (3-year survival: p16 absent 43% vs. 76% p16 retained; p = 0.0045).

Discussion

Recent advancements in molecular genetics have enhanced our understanding of glioma pathophysiology and clinical development, especially concerning their prognostic value and potential outcomes. The deletion of the CDKN2A/B gene, known to influence tumor progression and clinical outcomes, has been corroborated in other malignant central nervous system (CNS) neoplasms, including meningiomas [36, 45].

A previous meta-analysis pooled dichotomous data on CDKN2A/B deletions (tumor recurrence/death: yes or no) [22]. However, according to the Cochrane handbook, combining dichotomous data in conventional meta-analyses may lead to less reliable conclusions [16]. Instead, time-to-event data, especially with IPD, is recommended for more accurate meta-analyses [33]. Notably, the earlier meta-analysis by Lu et al. [22] did not use the now preferred method to reconstruct IPD. Therefore, we performed an IPD meta-analysis using longitudinal time-to-event data to more precisely assess the survival impact of CDKN2A/B deletions. We discovered that on average, 23.8% of gliomas have some form of CDKN2A/B deletion, either heterozygous or homozygous. Notably, 57.1% of IDH-wt GBM possess homozygous deletions, compared to only 9.8% in IDH-mut gliomas. These findings emphasize CDKN2A/B’s significant role in glioma progression and its effectiveness as a prognostic marker for OS in large IDH-wt and IDH-mut glioma cohorts.

The survival effect of intact CDKN2A/B in IDH-wt gliomas quantitatively reaches that of the survival benefit of the addition of temozolomide to radiotherapy in the “Stupp” trial in GBM (HR = 0.63) [37]. In IDH-mut gliomas the survival effect of intact CDKN2A/B resembles that of the survival benefit from post-radiation chemotherapy in low grade IDH-mut gliomas (HR = 0.38) in the RTOG9802 trial [3].

Homozygous deletions of CDKN2A/B emerge as potent biomarkers in gliomas, leading to uncontrolled cell cycle activity and increased cell proliferation [34], (Fig. S1 in Additional file 1). The CDKN2A/B genes encode three proteins that suppress the oncogenic cyclin-dependent kinase (CDK) pathway, with loss of function in proteins p14-p16 resulting in a dysregulated cell cycle and impacting other oncogenic pathways, including angiogenesis [7, 13]. For example, p14 inhibits endothelial cell migration by enhancing tissue inhibitor of metalloproteinase 3 expression [49], while p16 curtails angiogenesis by regulating vascular endothelial growth factors [13]. Additionally, heterozygous CDKN2A/B deletions in gliomas, detected in 17% of primary IDH-mut gliomas, hold prognostic significance akin to homozygous deletions, highlighting their relevance in glioma progression [18]. However, the lack of IPD hindered including this finding in our pooled analysis.

Our research corroborates the significant negative impact that homozygous deletion of CDKN2A has on the prognosis of patients with IDH-mut astrocytoma. Previous recent studies have noted that a homozygous deletion of CDKN2A/B correlates with a particularly adverse outcome in these patients, even among those with CNS WHO grade 4 tumors [10, 19, 35, 46]. Therefore, our results reinforce the notion that this genetic alteration serves as an independent marker for CNS WHO grade 4 pathologies [21]. The current WHO classification recommends testing for CDKN2A/B homozygous deletion in IDH-mut astrocytomas that exhibit anaplastic characteristics of CNS WHO grade 3. This recommendation does not extend to IDH-mut ODG that are neuropathologically consistent with CNS WHO grade 2 gliomas [21], as these typically do not have the CDKN2A/B homozygous deletion [35].

With increasing complexity and costs there is significant need for surrogate markers for CDKN2A/B deletions/alterations that can easily be tested. A recent investigation of 100 IDH-wt and IDH-mut gliomas cases showed a good correlation between p16 immunostaining and the presence of homozygous CDKN2A deletions across IDH-wt and IDH-mut tumors of all WHO grades. In tumors with neuropathologist-scored p16 greater than 20%, they found 100% specificity for excluding homozygous CDKN2A deletions, and in tumors with p16 equal to or less than 5%, they observed 100% specificity for predicting homozygous CDKN2A deletions. Hence, this study concluded that p16 immunohistochemistry is a cost effective and convenient method for evaluating CDKN2A homozygous deletions in gliomas, as an alternative to expensive genomic sequencing [44].

In our pooled analysis of all available p16 immunohistochemistry test results, these had a Youden’s Index of 0.59 and 79.0% sensitivity and 80.1% specificity for true cases of CDKN2A deletions. A 21% chance of errors persisted, emphasizing the need for corroborating tests and eventually standardized methods with clear cut-offs in this important field. A cut-off value of 5% demonstrated the highest diagnostic accuracy across all test parameters, especially in terms of sensitivity and PPV, to reliably identify affected patients. Regarding glioma subtype the accuracy was higher in IDH-mut glioma potentially explained by the increased cellular heterogeneity observed in IDH-wt GBM, including areas of necrosis and other structural variations. The low PPV alongside high sensitivity and NPV in IDH-mut glioma and astrocytoma appears due to the data distribution, with relatively high false positives reducing PPV, while low false negatives and high true negatives support high sensitivity and NPV. Where available, survival outcomes among glioma patients varied based on p16 status. Eventually, its cost-effectiveness and accessibility might make p16 immunohistochemistry a preferred preliminary screening tool, especially where genetic testing is less available. Further, it might be a valuable option for refined prognostic assessment in patients with IDH-wt GBM and an age ≥ 55 years where genetic testing is currently regarded as not-necessary according to recommendations of the WHO classification [47].

However, its ability to detect functional inactivation of CDKN2A/B through nonsynonymous CDKN2A/B mutation, which have recently been encountered in 2.6% of IDH-mut astrocytoma cases, or of heterozygous deletions might be reduced [15, 28]. Further investigation is needed to determine the significance of p16 effects, not tied to CDKN2A/B deletion but due to alternative inactivation mechanisms, such as truncating mutations or hypermethylation.

Our results underscore the necessity for future research to implement more uniform p16 scoring methods to increase comparability. Developing definitive guidelines for p16 retention thresholds would enhance the reliability of p16 IHC as a prognostic indicator for CDKN2A/B deletions. Against this backdrop, the present pooled results still must be interpreted with caution due to heterogeneous methodology regarding cut-off determination in p16 IHC.

Prognostication by biomarkers is the first step to establish novel targeted therapies. However, the implications of CDKN2A/B deletion status regarding survival is complex in the novel stratification of gliomas by the IDH status.

The influence of IDH mutations on glioma outcomes is closely linked to the status of tumor-suppressor genes. The anti-tumor effect of IDH mutations is nullified by CDKN2A/B deletion, diminished with TP53 mutations or 1p/19q codeletions, and strongest with intact tumor-suppressor genes (Fig. S2 in Additional file 1). Essentially, the presence of CDKN2A/B deletion marks a critical decline in prognosis for IDH-mut gliomas [2, 22, 35]. Without this deletion, TP53 mutations in IDH-mut astrocytomas correlate with reduced survival compared to TP53-wildtype [24], underscoring the role of tumor-suppressor genes in cancer progression. Conversely, in tumors with intact TP53 and CDKN2A, IDH1 mutations significantly inhibit glioma development [41]. Thus, the loss of key tumor-suppressor genes, especially CDKN2A/B, undermines IDH mutation’s suppressive effects concerning more aggressive glioma types.

The recent meta-analysis faces several limitations. The data of four clinical studies was included, which represents a limited dataset, especially with regards to analysis of potential confounding effects. However, data of 714 patients (212 IDH-wt GBM and 502 IDH-mut astrocytoma) was accumulated which exceeds the usual patient number of large clinical trials and adds significant accuracy to the effect estimations of individual studies. The included studies predate the latest WHO CNS tumor classification [21] and lacked refinement in individual patient data across crucial factors such as MGMT promoter methylation, resection extent, and treatment specifics. Despite this, data stratification by IDH status provided a substantial cohort of IDH-mut gliomas. Variability in resection extent among studies could affect detected deletion rates and PFS evaluations [8]. Detection methods for CDKN2A/B deletions vary in precision, employing techniques like SNP microarrays, NGS, methylation studies, and FISH. Integrating CDKN2A and CDKN2B analyses through NGS for targeted and whole-genome approaches, and using methylation arrays like HumanMethylation450 and MethylationEPIC, enhances diagnostic accuracy but can result in inter-lab result discrepancies. Genome-wide methylation analysis also offers significant prognostic data [26]. It is crucial to assess and compare these methodologies for their predictive accuracy in PFS and OS [48].

In conclusion, the present meta-analysis is the first investigation using reconstructed IPD to analyze the impact of homozygous CDKN2A/B deletions on OS in 714 IDH-wt or IDH-mut gliomas. The results prove that homozygous CDKN2A/B deletions are strong negative prognostic markers for OS in both IDH-mut and IDH-wt gliomas. P16 immunohistochemistry seems to be a promising surrogate tool with varying accuracy depending on cut-offs and tumor types. The standardization of scoring and detection of other functionally relevant CDKN2A/B alterations needs to be further investigated. Eventually, these findings might provide information that aid future clinical studies investigating targeted drug therapies for IDH-mut/IDH-wt gliomas with CDKN2A/B gene alterations.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BEV:

Bevacizumab

CDK:

Cyclin-Dependent Kinase

CDKN2A/B:

Cyclin-Dependent Kinase Inhibitor 2 A/2B

CI:

Confidence Interval

CNS:

Central Nervous System

FISH:

Fluorescence In Situ Hybridization

GBM:

Glioblastoma

HR:

Hazard Ratio

IHC:

Immunohistochemistry

IDH:

Isocitrate Dehydrogenase

IPD:

Individual Patient Data

MTAP:

Methylthioadenosine Phosphorylase

NGS:

Next Generation Sequencing

NPV:

Negative Predictive Value

ODG:

Oligodendroglioma

OS:

Overall Survival

PPV:

Positive Predictive Value

PFS:

Progression-Free Survival

SNP:

Single Nucleotide Polymorphism

TMZ:

Temozolomide

WHO:

World Health Organization

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Acknowledgements

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Funding

No funding was received to assist with the preparation of this manuscript.

Open Access funding enabled and organized by Projekt DEAL.

Author information

Author notes

  1. Darius Noack and Johannes Wach contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, University Leipzig Medical Center, Stephanstraße 9a, 04103, Leipzig, Germany

    Darius Noack, Nils H. Nicolay & Clemens Seidel

  2. Department of Neurosurgery, University Leipzig Medical Center, 04103, Leipzig, Germany

    Johannes Wach & Erdem Güresir

  3. Paul-Flechsig Institute of Neuropathology, University Leipzig Medical Center, 04103, Leipzig, Germany

    Alonso Barrantes-Freer

  4. Comprehensive Cancer Center Central Germany (CCCG), 04103, Leipzig, Germany

    Darius Noack, Nils H. Nicolay & Clemens Seidel

Authors
  1. Darius Noack
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  2. Johannes Wach
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  3. Alonso Barrantes-Freer
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  4. Nils H. Nicolay
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  5. Erdem Güresir
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  6. Clemens Seidel
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Contributions

Conceptualization, Darius Noack, Johannes Wach and Clemens Seidel; Data curation, Darius Noack, Johannes Wach and Clemens Seidel; Formal analysis, Darius Noack, Johannes Wach, Clemens Seidel; Investigation, Darius Noack, Johannes Wach and Clemens Seidel; Methodology, Darius Noack, Johannes Wach and Clemens Seidel; Resources, Alonso Barrantes-Freer, Nils H. Nicolay, Erdem Güresir, Johannes Wach and Clemens Seidel; Supervision, Erdem Güresir, Nils H. Nicolay and Clemens Seidel; Validation, Johannes Wach and Clemens Seidel; Writing – original draft, all authors; Writing – review & editing, all authors. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Clemens Seidel.

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Noack, D., Wach, J., Barrantes-Freer, A. et al. Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing. acta neuropathol commun 12, 180 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40478-024-01889-7

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Keywords

Acta Neuropathologica Communications

ISSN: 2051-5960

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