Molecular and histologic characteristics of pseudoprogression in diffuse gliomas

During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8?%). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11?%). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21?%. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90?%) and had a low rate of IDH1 R132H mutation (50?%). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.     

Assessing CpG island methylator phenotype, 1p/19q codeletion,and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial

Background

Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay.

Methods

Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial.

Results

Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases.

Conclusions

G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing.     

Clinical value of chromosome arms 19q and 11p losses in low-grade gliomas

Background

Diffuse low-grade gliomas (LGGs) form a heterogeneous subgroup of gliomas in adults. Chromosome (chr) arms 1p/19q codeletion and IDH mutation have been shown to be closely associated with oligodendroglial phenotype and better prognosis. We sought to identify relevant biomarkers in non 1p/19q codeleted LGGs.

Methods

We characterized a retrospective series of 126 LGGs using genomic arrays, microsatellite analysis, IDH sequencing, MGMT promoter methylation assay, and p53 expression analysis.

Results

Our study confirms that 1p/19q codeletion, mutually exclusive with p53 overexpression, was associated with: (i) better prognosis, (ii) oligodendroglial phenotype, (iii) MGMT promoter methylation, and (iv) IDH mutation. Interestingly, 1p/19q codeleted tumors occur in older patients at diagnosis. Our study shows that non 1p/19q codeleted LGGs can be divided in 5 main genomic subgroups: (i) 11p loss, (ii) 19q loss (iii) 7 gain, (iv) 19 gain, and (v) unclassified. In non 1p/19q codeleted LGGs, we demonstrated that (i) 11p loss is associated with astrocytoma phenotype and has an independent negative prognostic value, and (ii) 19q loss diminished the favorable prognostic value of IDH mutation. Our findings were validated in an independent cohort of 98 LGGs.

Conclusion

Novel genomic entities and biomarkers have been identified in non 1p/19q codeleted LGGs. Our findings may help to stratify non 1p/19q codeleted LGGs, facilitating future individualization of treatment. Further prospective studies are warranted to support our findings.     

Primary glioblastoma with oligodendroglial differentiation has better clinical outcome but no difference in common biological markers compared with other types of glioblastoma

Background

Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification—however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation.

Methods

We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome.

Results

GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P = .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P = .005). Singular LOH of 19q (P = .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P = .8, P = 1.0, P = 1.0, respectively).

Conclusions

Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM.     

Co-polysomy of chromosome 1q and 19p predicts worse prognosis in 1p/19q codeleted oligodendroglial tumors: FISH analysis of 148 consecutive cases

Background

This study aimed to evaluate the prognostic significance of co-polsomy of chromosome 1q and 19p in 1p/19q codeleted oligodendroglial tumors (ODGs).

Methods

In a series of 148 ODGs with 1p/19q deletion, co-polysomy of 1q and 19p was detected by fluorescence in situ hybridization (FISH). Log-rank analysis and Cox regression methods were used to compare Kaplan–Meier plots and identify factors associated with worse prognosis.

Results

There were 104 (70.3%) low-grade ODGs and 44 (29.7%) high-grade ODGs. Co-polysomy was independently associated with shorter progression-free survival and overall survival in 1p/19q codeleted ODGs, irrespective of tumor grades. The odds ratio of without and with co-polysomy was 0.263 (95% confidence interval [CI], 0.089–0.771; P = .015) for progression-free survival and 0.213 (95% CI, 0.060–0.756; P = .017) for overall survival. Subgroup analysis confirmed this trend in both low-grade and high-grade ODGs, although the P value for high-grade ODGs was marginally significant.

Conclusions

Co-polysomy of 1q and 19p could be used as a marker to independently predict worse prognoses and guide individual therapy in 1p/19q codeleted ODGs.     

Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

Background

Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations.

Methods

Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.

Results

Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], “astrocytoma”), 49 as type I (1p/19q codeletion, “oligodendroglioma”), 55 as type III (7+/10q– or TERTmut and 1p/19q intact, “glioblastoma”), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.

Conclusion

Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.     

A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors

Glial tumors with oligodendroglial components are considered chemo-responsive. Forty newly diagnosed patients (11 anaplastic oligodendrogliomas [OD] and 29 anaplastic oligoastrocytomas [OA]) were enrolled into this multicenter, open-label, single-arm Phase II trial of first-line temozolomide (200 mg/m² on days 1–5 every 4 weeks for 6 cycles). The primary endpoint was 6-month progression-free survival (PFS) with response rate (RR), median PFS, and median overall survival (OS) as secondary endpoints. Of 39 evaluable patients at the 6-month time point (median follow-up, 34 months), 6-month PFS was 77% (95% confidence interval [CI], 74.5%–79.3%). There were 15 complete responses (CRs, 38%), 6 partial responses (PRs, 15%), and 9 disease stabilization (23%). The median PFS was 21 months (95% CI, 3–39 months), and the median OS was 43 months (95% CI, 20–66 months). Chromosome 1p/19q codeletions were seen in 47% (18 of 38) of the patients, and O-6-methylguanine-DNA-methyltransferase (MGMT) methylation was seen in 48% (10 of 21) of the patients. All patients with OD showed MGMT methylation and most (71%) had chromosome 1p/19q codeletions. Conversely, fewer patients with OA showed MGMT methylation (23%) or had chromosome 1p/19q codeletions (31%). The presence of either 1p/19q codeletion or MGMT methylation was associated with increased RR at 6 months but not with improved PFS or OS. Only 18% of the patients (7 of 40) experienced treatment-related grade 3/4 toxicities. This regimen was active and well tolerated. These data add to the growing body of data showing that primary chemotherapy may be an acceptable alternative to radiotherapy for patients with gliomas containing oligodendroglial histology.     

IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas

Background

Epigenetic, genetic, and molecular studies have identified several diagnostic and prognostic markers in diffuse gliomas. Their importance for evaluating WHO grade II gliomas has yet to be specifically delineated.

Methods

We analyzed markers, including IDH mutation(IDHmut), 1p19q codeletion(1p19qcodel), ATRX expression loss(ATRX loss) and p53 overexpression, and outcomes in 159 patients with WHO grade II oligodendroglioma, oligoastrocytoma, and astrocytoma (2003–2012).

Results

IDHmut was found in 141(91%) and ATRX loss in 64(87%) of IDHmut-noncodel tumors (p = 0.003). All codeleted tumors (n = 66) were IDHmut. Four subgroups were identified: IDHmut-codel, 66(43%); IDHmut-noncodel-ATRX loss, 60(39%); IDHmut-noncodel-ATRXwt, 9(6%); IDHwt, 14(9%). Median survival among 4 groups was significantly different (p = 0.038), particularly in IDHmut-codel (median survival 15.6 years) compared to the remaining 3 groups (p = 0.025). Survival by histology was not significant. Overall (OS), but not progression-free (PFS), survival was significantly longer with gross total resection vs. biopsy only (p = 0.042). Outcomes for patients with subtotal resection were not significantly different from those with biopsy only. Among these uniformly treated patients, OS far exceeds PFS, particularly in those with 1p/19q codeletion.

Conclusions

For WHO grade II diffuse glioma, molecular classification using 1p/19qcodel, IDHmut, and ATRX loss more accurately predicts outcome and should be incorporated in the neuropathologic evaluation.     

IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival

Background

Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period.

Methods

The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike''s information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations.

Results

Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05).

Conclusion

By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.     

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss,genomic instability,and angiogenic gene expression

Background

The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs).

Methods

The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays.

Results

Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2.

Conclusion

In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.     

Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence

Background

According to the Response Assessment in Neuro-Oncology criteria, new enhancement within the radiation field on contrast enhanced T1-weighted images within 12 weeks after completion of radiotherapy should not qualify for progressive disease, since up to 50% of these cases may be pseudoprogression (PsP). To validate this concept, we assessed incidence and overall survival (OS) of patients with suspected and confirmed PsP dependent on different time intervals and definitions of PsP.

Methods

Patients with newly diagnosed glioblastoma and an enhancement increase of at least 25% after completion of standard radiochemotherapy at month 1, 4, 7, or 10 were eligible. Based on the development of the enhancement in follow-up examinations, patients were categorized as either PsP (subgrouped as complete resolution/decrease >50% and decrease <50%/stable) or true progression.

Results

Out of 548 patients, 79 fulfilled the inclusion criteria. Of these 79 patients, 9 (11.4%) showed PsP (6/45 patients at 1 month, 2/17 at 4 months, 1/9 at 7 months, and 0/8 at 10 months). Complete resolution of the enhancement was found in 1, decrease >50% in 3, decrease <50% in 2, and stable enhancement in 3 patients with PsP. Patients with PsP showed a significantly longer OS (P < .012). No difference in OS was found among PsP subgroups.

Conclusions

This series challenges the current concept of PsP. Even though we could confirm a prolonged OS of patients with PsP, the incidence of PsP was lower than reported previously and extended beyond 12 weeks.     

Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors

Background

Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication.

Methods

We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis.

Results

Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 y, not codeleted), class III (age 43–59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43–59 y, not codeleted, not frontal lobe tumor or age 60–69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P < .0001), with medians ranging from 9.3 years (95% CI: 8.4–16.0) for class I to 0.6 years (95% CI: 0.5–0.9) for class V.

Conclusions

These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome.     

Mitotic index,microvascular proliferation,and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations

Background

The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs).

Methods

The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing.

Results

1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10⁻⁴), IDH1/2 mutation (P < 10⁻⁴), chromosome 4 loss (P < 10⁻³), and better overall survival (P < 10⁻⁴). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023).

Conclusions

The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations.     

1p/19q codeletion and IDH1/2 mutation identified a subtype of anaplastic oligoastrocytomas with prognosis as favorable as anaplastic oligodendrogliomas

Background

Anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA), and anaplastic oligodendroglioma (AO) are the major histological subtypes of World Health Organization grade III gliomas. More evidence suggests that AOA is unlikely to be a distinct entity, and re-evaluation of this issue has been recommended. In this study, we divided AOA into 2 subgroups, according to molecular biomarkers, and compared the survivals between them.

Methods

One hundred nine patients with histological diagnosis of anaplastic gliomas enrolled in the study. Molecular biomarkers evaluated included 1p/19q codeletion and IDH1/2 mutation. Kaplan-Meier plots were compared by log-rank method.

Results

There was no significant difference between AA and AOA with regard to the frequencies of biomarkers and survival plots. According to the status of biomarkers, AOA was classified into 2 subgroups (AOA1 and AOA2), for which Kaplan-Meier plots were significantly different (P = .001 for both progression-free survival [PFS] and overall survival [OS]). AOA1 with 1p/19q codeletion and/or IDH1/2 mutation showed similar Kaplan-Meier plots with AO (P = .169 for PFS and P = .523 for OS). AOA2 without either biomarker showed similar Kaplan-Meier plots with AA (P = .369 for PFS and P = .271 for OS). In addition, patients with AO and AOA1 had significantly longer PFS and OS than did patients with AA and AOA2 (P < .001 for both PFS and OS).

Conclusions

AOA is a heterogeneous group and can be divided into 2 subgroups with significantly different prognoses according to the status of 1p/19q and IDH1/2. This will be helpful in estimating patients'' prognosis and guiding reasonable therapy for patients with anaplastic gliomas.     

Analysis of IDH mutation, 1p/19q deletion,and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas

Background

Grades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal.

Methods

In this study, we analyzed a set of 108 nonenhancing hemispheric grade II–III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR).

Results

Patient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR.

Conclusions

We conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified.     

Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis

Background

Glioma is rarely curable, and factors that influence the prognosis of glioma patients are not fully understood. Loss of heterozygosity (LOH) of 1p/19q has long been known to be a typical molecular signature of oligodendroglial neoplasms. However, whether LOH of 1p/19q is associated with survival in gliomas remains controversial. Here our goal was to evaluate the association between LOH of 1p/19q and progression-free survival (PFS) and overall survival (OS) by conducting a meta-analysis among glioma cases.

Methods

The PubMed and Embase databases were searched from the earliest records to May 2013 to identify studies that met prestated inclusion criteria. Reference lists of retrieved articles were also reviewed. Three authors independently extracted information needed for further analysis. Either a fixed- or a random-effects model was used to calculate the overall combined hazard ratio (HR) estimates.

Results

Twenty-eight eligible studies involving 3 408 cases were included in the meta-analysis. Compared with the chromosomal intact group, codeletion of 1p and 19q was associated with a better PFS (HR = 0.63; 95% CI, 0.52–0.76) and OS (HR = 0.43; 95% CI, 0.35–0.53). Subgroup analyses showed this association to be independent of detection methods and the grades and subtypes of gliomas. Furthermore, isodeletion of chromosome 1p predicted a similar favorable disease outcome (PFS: HR = 0.68; 95% CI, 0.47–0.97) (OS: HR = 0.51; 95% CI, 0.35–0.75), especially in low-grade gliomas, whereas isodeletion of 19q only indicated longer PFS (HR = 0.70; 95% CI, 0.56–0.87).

Conclusion

Codeletion of 1p and 19q is associated with better survival rates in glioma. Isodeletion of 1p predicts similar outcomes but to a lesser extent, whereas the effects of isodeletion of 19q remained only marginal.     

MYCN amplification predicts poor outcome for patients with supratentorial primitive neuroectodermal tumors of the central nervous system

Background

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are a rare group of neoplasms occurring in the CNS that includes supratentorial CNS-PNETs, medulloepitheliomas, and ependymoblastomas. While ependymoblastomas frequently carry chromosome 19q13.41 amplification and show aggressive clinical behavior, the biological mechanisms and molecular alterations contributing to the pathogenesis of supratentorial CNS-PNETs remain poorly understood. Moreover, genetic alterations suitable for molecular risk stratification are undefined to date.

Methods

In order to identify possible molecular markers, we performed multiplex ligation-dependent probe amplification (MLPA) and molecular inversion probe (MIP) analysis on DNA samples of 25 supratentorial CNS-PNETs (median age, 5.35 years; range, 2.41–17.28 years). Tumors with ependymoblastic rosettes (ependymoblastoma/ETANTR) and LIN28A positivity were excluded.

Results

MLPA and MIP analysis revealed large losses of genomic material of chromosomes 3, 4, 5, and 13, while frequent gains affected chromosomes 1, 17, 19, 20, and 22. High copy number gains (amplifications) were found in particular at chromosomes 2p24.3 (MYCN, n = 6 cases) and 4q12 (n = 2 cases). Patients with tumors harboring 2p gain or MYCN amplification showed unfavorable overall survival (P = .003 and P = .001, respectively).These markers were independent of the presence of metastases, which was indeed a clinical factor associated with poor overall survival (P = .01) in this series.

Conclusions

In the era of the personalized neuro-oncology, the identification of these molecular prognostic markers associated with patient outcome may represent a significant step towards improved patient stratification and risk-adapted therapeutic strategies for patients suffering from supratentorial CNS-PNETs.     

The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

Background

Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O⁶-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients.

Methods

We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor.

Results

Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets.

Discussion

The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.     

Gene expression profiling identifies different sub-types of retinoblastoma

Background:

Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour.

Methods:

Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis.

Results:

Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation.

Conclusion:

Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.