The Epigenetic Regulator Jumonji Domain-Containing Protein 6 (JMJD6) Is Highly Expressed but Not Prognostic in IDH-Wildtype Glioblastoma Patients

Patients with IDH-wildtype glioblastoma (GBM) generally have a poor prognosis. However, there is an increasing need of novel robust biomarkers in the daily clinico-pathological setting to identify and support treatment in patients who become long-time survivors. Jumonji domain-containing protein 6 (JMJD6) is involved in epigenetic regulation of demethylation of histones and has been associated with GBM aggressiveness. We investigated the expression and prognostic potential of JMJD6 tumor fraction score in 184 IDH-wildtype GBMs. Whole-slides were double-stained with an antibody against JMJD6 and an exclusion-cocktail consisting of 4 antibodies (CD31, SMA, CD45, and Iba-1), enabling evaluation of tumor cells only. Stainings were quantified with a combined software- and scoring-based approach. For comparison, IDH-mutated WHO grade II, III and IV astrocytic gliomas were also stained, and the JMJD6 tumor fraction score increased with increasing WHO grade, although not significantly. In multivariate analysis including age, gender, performance status and post-surgical treatment high JMJD6 tumor fraction score was associated with longer overall survival in IDH-wildtype GBMs (p = 0.03), but the effect disappeared when MGMT promoter status was included (p = 0.34). We conclude that JMJD6 is highly expressed in IDH-wildtype GBM but it has no independent prognostic value.

NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to Temozolomide (TMZ) via NELFB and RPS6KB2 interaction.

Nop2/Sun RNA methyltransferase (NSUN6) is an RNA 5 - methyl cytosine (5mC) transferase with little information known of its function in cancer and response to cancer therapy. Here, we show that NSUN6 methylates both large and small RNA in glioblastoma and controls glioblastoma response to temozolomide with or without influence of the MGMT promoter status, with high NSUN6 expression conferring survival benefit to glioblastoma patients and in other cancers. Mechanistically, our results show that NSUN6 controls response to TMZ therapy via 5mC mediated regulation of NELFB and RPS6BK2. Taken together, we present evidence that show that NSUN6 mediated 5mC deposition regulates transcriptional pause (by accumulation of NELFB and the general transcription factor complexes (POLR2A, TBP, TFIIA, TFIIE) on the preinitiation complex at TATA binding site to control translation machinery in glioblastoma response to alkylating agents. Our findings open a new frontier into controlling of transcriptional regulation by RNA methyltransferase and 5mC.

Elderly glioblastoma patients: Survival analysis according adjuvant therapy and tumor molecular analysis.

e14046 Background: Glioblastoma (GBM) grade IV represents the most frequent and aggressive primary brain tumor. Despite complete surgical resection, GBM infiltrative potential leads to local recurrence rates of around 100%. Standard treatment with adjuvant chemotherapy (CT) and radiotherapy (RT) according Stupp regimen aims to reduce relapse and improve survival, but toxicities associated with these therapies represent a problem in elderly unfit population. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been recognized as a predictive factor of response to alkylating agents as temozolomide. We aimed to compare overall survival (OS) results in elderly GBM patients according with MGMT promoter status and systemic treatment after surgery. Methods: We performed a database from the information available from RETSINE (Registro Nacional Español de Tumores de Sistema Nervioso Central). We selected ≥ 65 years GBM diagnosed patients. Relevant information was tumor MGMT promoter methylation status and adjuvant CT and/or RT after resection. Kaplan- Meier analysis was performed. Selected outcome was OS and 95% confidence intervals (CI) and p value < 0.05 were used as measures of statistical significance. Results: We identified 400 eligible GBM patients diagnosed ≥ 65 years (male = 232- 58%; female = 168-42% ). According tumor MGMT status: 125 (31.3%) methylated tumors, 115 (28.7%) non methylated and 160 unknown MGMT status. Included population median age was 72 years (65-88 years). Median global population OS was 7.93 months (IC95% 6.84-9.02). Survival analysis showed better OS for methylated tumors group, median OS 7.33 (IC 95%4.1-10.56) vs. unmethylated OS 7.06 (IC95% 4.9-9.1) (p = 0.021). Survival analysis in methylated patients showed improved OS in patients treated with RT + CT vs. no adjuvant therapy. Median OS for methylated patients treated with CT + RT was 11.46m (IC95%7.6-15.9) vs 9.6 months with only RT(IC95%3.67-7.26) and 2.1m with no treatment (IC95%2.03-3.76) p = 0,00. Unmethylated patients median OS was 9.36m (IC95%3.67-7.26) for RT-CT, 5.4 m (IC95%2.37-8.42) for RT only and 2.76 (IC95% 1.37-4.15) for no treatment p = 0.00. Conclusions: Elderly GBM patients have similar treatment options than young patients and comprise surgical resection, RT and alkylating CT with temozolomide. Comorbidities and performance status have relevant implications in elderly population treatment decisions. The MGMT promoter status has been described as a prognostic and predictive marker of response to temozolomide. In our series both methylated and unmethylated patients can benefit with systemic treatment.

P13.02 Conventional MRI radiomics in the diagnosis of early- and pseudo-progression

BACKGROUND After radiochemotherapy, 20% to 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic performance and survival predictive ability of radiomics in patients with suspected EP or Psp. MATERIAL AND METHODS Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis and, forecasts were evaluated using C index and integrated Brier scores (IBS). RESULTS Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively in training and validation phases. Addition of MGMT promoter status improved accuracy to 83% and 79.2% and, specificity to 63.6% and 75%. OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio (HR), 3.63, p=0.002) and the validation (HR, 3.76, p=0.001) phases. Similarly, PFS model stratified patients during training (HR, 2.58, p=0.005) and validation (HR, 3.58, p=0.004) phases using 5 RF. OS and PFS forecasts had C index of 0.65 and 0.69 and IBS of 0.122 and 0.147, respectively. CONCLUSION Conventional MRI radiomics has promising diagnostic value, especially when combined with MGMT promoter status, but specificity remains moderate. In addition, our results suggest a potential for predicting OS and PFS.

Conventional MRI radiomics in patients with suspected early- or pseudo-progression

Background After radiochemotherapy, 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic value of radiomics in patients with suspected EP or Psp. Methods Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis, and forecasts were evaluated using C-index and integrated Brier scores (IBS). Results Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively, in training and validation phases. Addition of MGMT promoter status improved accuracy to 83% and 79.2%, and specificity to 63.6% and 75%. OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio [HR], 3.63; P = .002) and the validation (HR, 3.76; P = .001) phases. Similarly, PFS model stratified patients during training (HR, 2.58; P = .005) and validation (HR, 3.58; P = .004) phases using 5 RF. OS and PFS forecasts had C-index of 0.65 and 0.69, and IBS of 0.122 and 0.147, respectively. Conclusions Conventional MRI radiomics has promising diagnostic value, especially when combined with MGMT promoter status, but with moderate specificity. In addition, our results suggest a potential for predicting OS and PFS.

Antiangiogenic Therapies and Extracranial Metastasis in Glioblastoma: A Case Report and Review of the Literature

We present a case report of a patient with glioblastoma multiforme (GBM) complicated by extracranial metastasis (ECM) whose survival of nearly four years surpassed the anticipated life expectancy given numerous negative prognostic factors including EGFRvIII-mutation, unmethylated MGMT promoter status, and ECM. Interestingly, while this patient suffered from locally aggressive disease with multiple intracranial recurrences, the proximal cause of death was progressive extracranial disease and complications related to pulmonary metastases. Herein, we review potential mechanisms of ECM with an emphasis upon glioblastoma molecular and genetic profiles and the potential implications of targeted agents such as bevacizumab.