Molecular prognostic factors of anaplastic oligodendroglial tumors and its relationship: a single institutional review of 77 patients from China

The increased chemosensitivity of oligodendroglial tumors has been associated with loss of heterozygosity (LOH) on chromosomes 1p and 19q. Other clinical and molecular factors have also been identified as being prognostic and predictive for treatment outcome. Seventy-seven patients with anaplastic oligodendroglioma (AO) or anaplastic oligoastrocytoma (AOA), treated in Beijing Tiantan Hospital from 2006 through 2008, were reviewed. LOH 1p, LOH 19q, IDH1 mutation, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and protein expression level of MGMT, P53, EGFR, and Ki-67 were evaluated. Age at diagnosis, LOH 1p and 19q, IDH1 mutation, P53 expression level, reoperation when progression, and adjuvant chemotherapy were statistically significant factors for overall survival (OS) in univariate analysis. Further multivariate analysis showed that age at diagnosis (P = .010), LOH 1p and 19q (P = .016), IDH1 mutation (P = .011), and reoperation after progression (P = .048) were independent predictors for longer survival in these patients. Nonrandom associations were found between LOH 1p and LOH 19q, MGMT promoter methylation and LOH 1p or 19q, IDH1 mutation and LOH 1p and 19q, IDH1 mutation and MGMT promoter methylation, whereas mutual exclusion was found between MGMT promoter methylation and MGMT expression level. The present study confirmed that age at diagnosis, LOH 1p and 19q, IDH1 mutation, and reoperation after progression were independent significant prognostic factors for patients with anaplastic oligodendroglial tumors. Inter-relationship between LOH 1p, LOH 19q, IDH1 mutation, MGMT promoter methylation, and MGMT expression level were also revealed. Future clinical trials for AO and AOA should consider the molecular alterations of patients.     

IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma

Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58/79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma.     

少突胶质细胞瘤中染色体1p/19q联合缺失与MGMT基因启动子甲基化的相关性

目的 研究少突胶质细胞瘤染色体1p/19q联合缺失与MGMT基因启动子甲基化的相关性。方法 选取少突胶质细胞瘤35例、间变型少突胶质细胞瘤32例标本作为实验组,星形细胞瘤20例及瘤旁正常脑组织标本20例作为对照组,荧光原位杂交方法检测染色体1p/19q联合缺失情况,巢式甲基化特异性PCR技术检测MGMT基因启动子甲基化情况。结果 少突胶质细胞瘤和间变型少突胶质细胞瘤1p/19q联合缺失率分别为85.71%、75.00%,均显著高于星形细胞瘤及正常脑组织（P<0.05）;少突胶质细胞瘤、间变型少突胶质细胞瘤、星形细胞瘤的MGMT基因启动子甲基化率均显著高于正常脑组织（P<0.05）,但三者组间比较差异无统计学意义（P>0.05）;少突胶质细胞瘤1p/19q联合缺失与MGMT基因启动子甲基化呈正相关性,并且均与患者3年生存率相关（P<0.05）。结论 少突胶质细胞瘤中1p/19q联合缺失与MGMT基因启动子甲基化状态密切相关,联合检测有助于提高临床病理诊断的精确性,更好地评估预后。     

Combining two biomarkers, IDH1/2 mutations and 1p/19q codeletion, to stratify anaplastic oligodendroglioma in three groups: a single-center experience

IDH1/2 mutations and 1p/19q codeletion occur frequently in anaplastic gliomas and are prognostic factors. We combined these two biomarkers to stratify patients treated for anaplastic oligodendroglioma (AO). 43 consecutive WHO AO were selected. We combined immunohistochemistry (IHC) with the monoclonal antibody mIDH1R132H and DNA sequencing of IDH1 and IDH2 genes. Fluorescence in situ hybridization was carried out to evaluate 1p/19q codeletion. These biomarkers were correlated with progression-free survival (PFS) and overall survival (OS). IDH1/IDH2 mutations occurred in 23/43 (54 %) patients: 20/43 IDH1-R132H mutation in IHC, 2/43 IDH1-R132G mutation and 1/43 IDH2-R172K mutation identified by DNA sequencing. 1p/19q codeletion was detected for 23/43 patients. With median follow-up of 19 months (range 1.4–128), median PFS and OS were 22 and 35 months respectively. IDH1/IDH2 mutations were strongly associated with improved PFS and OS: 5-year PFS was 86 versus 6 % and 5-year OS was 91 versus 9 % for patients with IDH1/IDH2 mutations versus wild-type IDH respectively. In multivariate analyses, IDH1/IDH2 mutations and 1p/19q loss were independent prognostic factors. Three groups with distinct prognostic features were identified: patients with IDH1/2 mutations and 1p/19q loss (median PFS, median OS not reached), patients with IDH1/2 mutations or 1p/19q loss (median PFS: 22 months, median OS: 30 months), and patients without IDH1/2 mutations nor 1p/19q loss with a bad prognosis (median PFS: 8.6 months, median OS: 9.9 months). Combining two biomarkers, IDH1/2 and 1p/19q codeletion, makes it possible to stratify AO in three groups with very distinct prognostic features.     

Differential molecular genetic analysis in glioblastoma multiforme of long- and short-term survivors: a clinical study in Chinese patients

This study was designed to find whether long-term survivors (LTSs) exhibit molecular genetic differences compared with short-term survivors (STSs) in patients with GBM. Tumors from 12 patients initially diagnosed with GBM and survived longer than 36 months (LTSs) were compared with 30 patients with GBM and STSs (survival <18 months) for detecting of MGMT promoter methylation, 1p/19q LOH and IDH1 mutation. IDH1 mutation and MGMT promoter methylation were significantly more frequent in the LTSs group (P = 0.039 and 0.017, respectively). The incidence of 1p/19q co-deletion was not significantly different (P = 1.0). IDH1 mutation and MGMT promoter methylation might be independent, significant, and favorable factors for LTSs with GBM.     

IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy

Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12–89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8–63.2) and 38 % (95 % CI, 25.7–50.7 %), and median and 5-year progression-free survival rates were 36 months (95 % CI, 28.5–44.0) and 22 % (95 % CI, 10–34 %), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60 % of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.     

Correlation of Molecular Markers in High Grade Gliomas with Response to Chemo-Radiation

Background: The standard of care in high grade glioma (HGG) is maximal safe surgical resection followed by adjuvant radiotherapy (RT) with/without chemotherapy. For anaplastic gliomas, studies have shown use of procarbazine, lomustine, vincristine (PCV) improves overall survival (OS) and progression free survival (PFS). Currently, there is substantial evidence that molecular markers strongly predict prognosis and response to treatment. Methods: Between January 2016 to January 2018, 42 patients were accrued and followed up till April 2019. The primary end points were to correlate molecular markers with response to therapy in terms of OS and PFS in HGG. The secondary end point was to evaluate frequency of 1p/19q codeletion, IDH 1 mutation, ATRX deletion and p53 in HGG patients. Results: The median age was 46 years (range 18-67) with M:F ratio 30:12. The frequency of IDH1 mutation,1p/19q codeletion, p53 mutation and ATRX mutation were 42.8%, 16.6%, 42.8% and 14.2% respectively. All the seven patients with 1p/19q codeletion had IDH1 mutation. Median follow up was 22 months. The 20-months PFS for different mutations were as follows; IDH1-mutated vs wild type: 53.6% vs 29.8%; p-0.035, 1p/19q codeleted vs non-codeleted: 85.7% vs 62.3%; p-0.011, p53 wild type vs mutated 32.1% vs 35.6%; p-0.035 and ATRX lost vs retained: 55.6% vs 53.3%; p- 0.369. The 20-months OS for IDH1 mutated vs wild type: 82.4% vs 30.6%; p-0.014, 1p/19q codeleted vs non-codeleted: 85.7% vs 65.8%; p-0.104, p53 wild-type vs mutated 45.5% vs 73.9%; p-0.036 and ATRX lost vs retained: 100% vs 60.3%; p-0.087. Conclusion: Codeletion of 1p/19q with IDH1 mutation in HGG is associated with a significantly favourable PFS. However, larger studies with longer follow up are required to evaluate OS and PFS in all the molecular subgroups.     

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1–5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.     

Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI

Although 1p19q codeleted gliomas are the most favorable molecular subgroup of lower-grade gliomas, there are cases with early recurrence or short survival. The objective of this study was to elucidate molecular–genetic and clinicopathological prognostic factors in patients with gliomas showing total 1p19q loss. The study included 57 consecutive patients with codeleted gliomas who were operated at Keio University Hospital between 1990 and 2010. These patients were assessed for chromosomal copy number aberrations, promoter methylation status of the O6-methylguanine-DNA methyltransferase gene (MGMT), and demographic and clinicopathological prognostic factors in diffuse gliomas. No significant difference was observed in the overall survival (OS) of the patients with respect to age (≥40 years vs. <40 years), degree of resection, maximum tumor diameter (≥5 cm vs. <5 cm), histological subtype, and MGMT promoter methylation status. Gain of chromosome 19p and grade III histology were associated with shorter OS (P?=?0.019, 0.061, respectively). Gain of 19p and histological grade III might be negative prognostic factors for the patients with gliomas showing total 1p19q loss. Further investigation is warranted to confirm these notions.     

Quantitative analysis of O<Superscript>6</Superscript>-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas

Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200 mg/m² on days 1–5 in a 4 week cycle. The median progression-free survival was 32 months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II gliomas.     

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.     

MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

AimsTo investigate the correlation between O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma.Patients and methodsA real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence.ResultsA subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p = 0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p < 0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma.ConclusionsMGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.     

Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951

BACKGROUND:

Although it has been demonstrated that the neuronal intermediate filament alpha‐internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs).

METHODS:

INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression‐free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O‐6 methylguanine‐DNA methyltransferase (MGMT) promoter methylation status.

RESULTS:

INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV.

CONCLUSIONS:

In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. Cancer 2011. © 2011 American Cancer Society.     

International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.     

Molecular profile of oligodendrogliomas in young patients

Several studies on molecular profiling of oligodendrogliomas (OGs) in adults have shown a distinctive genetic pattern characterized by combined deletions of chromosome arms 1p and 19q, O6-methylguanine-methyltransferase (MGMT) methylation, and isocitrate dehydrogenase 1 (IDH1) mutation, which have potential diagnostic, prognostic, and even therapeutic relevance. OGs in pediatric and young adult patients are rare and have been poorly characterized on a molecular and biological basis, and it remains uncertain whether markers with prognostic significance in adults also have predictive value in these patients. Fourteen cases of OGs in young patients (age, ≤ 25 years) who received a diagnosis over 7 years were selected (7 pediatric patients age ≤ 18 years and 7 young adults aged 19-25 years). The cases were evaluated for 1p/19q status, MGMT promoter methylation, p53 mutation, and IDH1 mutation. None of the pediatric cases showed 1p/19q deletion. In young adults, combined 1p/19q loss was observed in 57% and isolated 1p loss in 14% of cases. The majority of cases in both subgroups (71% in each) harbored MGMT gene promoter methylation. TP53 and IDH1 mutations were not seen in any of the cases in both the groups. To our knowledge, this is the first study to show that molecular profile of OGs in pediatric and young adult patients is distinct. Further large-scale studies are required to identify additional clinically relevant genetic alterations in this group of patients.     

Survival in glioblastoma: a review on the impact of treatment modalities

Glioblastoma (GBM) is the most common and lethal tumor of the central nervous system. The natural history of treated GBM remains very poor with 5-year survival rates of 5 %. Survival has not significantly improved over the last decades. Currently, the best that can be offered is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. Prognostic factors involved in survival include age, performance status, grade, specific markers (MGMT methylation, mutation of IDH1, IDH2 or TERT, 1p19q codeletion, overexpression of EGFR, etc.) and, likely, the extent of resection. Certain adjuncts to surgery, especially cortical mapping and 5-ALA fluorescence, favor higher rates of gross total resection with apparent positive impact on survival. Recurrent tumors can be offered re-intervention, participation in clinical trials, anti-angiogenic agent or local electric field therapy, without an evident impact on survival. Molecular-targeted therapies, immunotherapy and gene therapy are promising tools currently under research.     

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.     

Molecular genetic markers as predictors of response to chemotherapy in gliomas

PURPOSE OF REVIEW: This review summarizes recent studies on applications of molecular markers such as chromosome 1p/19q codeletion and MGMT status in the treatment of glioma. RECENT FINDINGS: Prospective trials confirmed that 1p/19q codeletion represents a strong and independent favourable prognostic factor in anaplastic oligodendroglial tumours. Other retrospective studies have suggested that 1p/19q loss is also predictive of chemosensitivity to alkylating agents (nitrosoureas and temozolomide) in low-grade gliomas. Recent reports have provided evidence that 1p and 19q deletions are mediated by unbalanced translocation. The targeted genes remain to be identified, however. Promoter methylation of MGMT gene silencing has been shown to predict benefit from chemotherapy in glioblastoma. MGMT promoter methylation and low expression of MGMT-encoded protein are frequently observed in low-grade gliomas and anaplastic oligodendroglial tumours. In such tumours, however, preliminary studies have yielded contradictory results on the predictive value of MGMT status regarding objective response to chemotherapy and correlation with 1p/19q deletion. SUMMARY: There is mounting evidence that 1p/19q deletion and MGMT inactivation are relevant prognostic markers and predictors of chemosensitivity in gliomas. Although such markers remain to be formally validated by ongoing and planned prospective trials, it is likely that they will soon become essential for optimizing treatment decisions.