Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH‐wildtype glioblastoma

Abstract

Objective Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH‐wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre‐ and post‐BEV eras. Methods We analyzed the data of 100 adult patients (over 18 years old) with IDH‐wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients’ OS. Results CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre‐BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post‐BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. Conclusions MGMT and CDKN2A status subdivided our cohort into three race‐specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion.

Volumetric study reveals the relationship between outcome and early radiographic response during bevacizumab-containing chemoradiotherapy for unresectable glioblastoma

“…McDonald's standard was created based on the WHO oncology response criteria, which is a general diagnostic imaging standard for solid tumors [ 33 ]; therefore, the measurement protocol for contrast-enhancement lesions has not been changed for more than 20 years. Our results propose the possibility that some patients evaluated as SD by the RANO criteria may have a good prognosis and suggest an alternative threshold value for identifying the group with a good prognosis [ 26 ].…”

“…In the present study, univariate analysis for molecular markers revealed an unmethylated MGMT status, and CDKN2A homozygous deletion showed a trend toward poor prognosis. Our recent study also reported that MGMT and CDKN2A status could stratify Japanese GBM patients into three race-specific groups with different prognoses [ 26 ]. Further accumulation of studies including molecular-genetic signatures and evidence beyond real-clinic data are warranted to evaluate the significance of image changes during BEV-included regimens for unresectable GBM.…”

“…Sample preparations and subsequent confirmation of genetic signatures whose clinical significance was revealed in previous studies, including ours, were performed as described previously [17][18][19][20][21][22][23][24][25]. The status of TP53, EGFR, PTEN, and CDKN2A was evaluated using the MLPA kit P105-2 according to our previous study [26].…”

Classification of adult‐type diffuse gliomas: Impact of the World Health Organization 2021 update

“…Additional molecular alterations have been associated with prognostic relevance in glioblastoma, although results are less than unanimous. CDKN2A/B loss has been linked with reduced overall survival; however, some studies have found this to be true only in tumors without MGMT methylation [76,77]. Recent work has also demonstrated variable associations between TERT mutation and unfavorable clinical course [77,78].…”

Intraventricular mucin‐producing glioblastoma arising in the septum pellucidum at the frontal horn of the lateral ventricle: A case report

“…D2-0217; MRC Holland, Amsterdam, The Netherlands) according to our previous study. 22 As a result, TP53 and NFKBIA deletions were detected (Fig. 4).…”