Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’‐like features associated with younger age

Ostrom, Quinn T.; Kinnersley, Ben; Armstrong, Georgina; Rice, Terri; Chen, Yanwen; Wiencke, John K.; McCoy, Lucie; Hansen, Helen M.; Amos, Christopher I.; Bernstein, Jonine L.; Claus, Elizabeth B.; Eckel‐Passow, Jeanette E.; Il’yasova, Dora; Johansen, Christoffer; Lachance, Daniel H.; Lai, Rose; Merrell, Ryan; Sadetzki, Siegal; Schildkraut, Joellen M.; Shete, Sanjay; Rubin, Joshua B.; Andersson, Ulrika; Rajaraman, Preetha; Chanock, Stephen J.; Linet, Martha S.; Wang, Zhaoming; Yeager, Meredith; Houlston, Richard S.; Jenkins, Robert B.; Wrensch, Margaret; Melin, Beatrice; Bondy, Melissa L.; Barnholtz‐Sloan, Jill S.

doi:10.1002/ijc.31759

Cited by 22 publications

(9 citation statements)

References 27 publications

(68 reference statements)

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“…The proneural GBM subtype is associated with improved prognosis [ 13 ], but is an uncommon entity in eGBM [ 14 ]. eGBM lack the isocitrate dehydrogenase ( IDH ) mutations [ 15 ] that confer survival advantage [ 16 , 17 ] and are rarely found in gliomas of older patients [ 17 – 19 ]. Only 3 of 126 gliomas of older patients in the Neurooncology Working Group (NOA) of the German Cancer Society Study 8 (NOA-08) [ 20 ] and 2 of 299 gliomas of older patients in the Nordic trials were found to have an IDH R132H mutation [ 21 ].…”

Section: Molecular Signature Of Gbm In Older Adultsmentioning

confidence: 99%

Newly Diagnosed Glioblastoma in Elderly Patients

2022

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Purpose of Review Elderly patients with newly diagnosed glioblastoma (eGBM) carry a worse prognosis compared with their younger counterparts. eGBM garners special attention due to the unique challenges, including increased treatment-associated toxicity, less relative benefit from aggressive therapy, medical comorbidities, and immunosuppression. The pivotal GBM trials excluded patients > 70 years old and the optimal treatment approach remains unsettled for eGBM. In this review, we analyze the historical evidence-based data for treating eGBM and discuss the future direction for managing this vulnerable population. Recent Findings Treatment for eGBM continues to evolve. Therapy choice is guided by performance status and presence of O6-methylguanine-DNA-methyltransferase ( MGMT ) promoter methylation. For eGBM with good performance status, combinatorial hypofractionated radiation therapy (hRT) and temozolomide should be recommended. For those with poor performance status, further stratification based on MGMT promoter methylation test result is recommended. Single-agent temozolomide is a viable treatment option for MGMT methylated tumors (m MGMT ); in particular, those classified with receptor tyrosine kinase II methylation. hRT alone can be considered in MGMT unmethylated (u MGMT ) eGBM patients. As precision oncology continues to advance, effective targeted and immunotherapy may emerge as new treatment options for eGBM. Summary Management of elderly patients with newly diagnosed GBM carries a unique set of challenges. Progress has been made in defining the optimal therapeutic approach for these patients, but many questions remain to be answered.

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Section: Molecular Signature Of Gbm In Older Adultsmentioning

confidence: 99%

Newly Diagnosed Glioblastoma in Elderly Patients

2022

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“…Some other studies have also used diverse features to depict the common and different features for GBM and LGG. There was a higher prevalence of “LGG”‐like tumor characteristics in GBM samples in those patients that were 18–53 years old . Overall, we integrated comprehensive molecular characteristics to identify GBM‐ and LGG‐specific genes.…”

Section: Discussionmentioning

confidence: 99%

“…There was a higher prevalence of "LGG"-like tumor characteristics in GBM samples in those patients that were 18-53 years old. 43 Overall, we integrated comprehensive molecular characteristics to identify GBM-and LGG-specific genes. Our analysis provides novel insights that can be used to study the mechanisms of and treatment for GBM and LGG.…”

Section: Discussionmentioning

confidence: 99%

Integrating multiple‐level molecular data to infer the distinctions between glioblastoma and lower‐grade glioma

Zhang

Liu

et al. 2019

Intl Journal of Cancer

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Glioblastomas (GBMs) and lower‐grade gliomas (LGGs) are the most common malignant brain tumors. Despite extensive studies that have suggested that there are differences between the two in terms of clinical profile and treatment, their distinctions on a molecular level had not been systematically analyzed. Here, we investigated the distinctions between GBM and LGG based on multidimensional data, including somatic mutations, somatic copy number variants (SCNVs), gene expression, lncRNA expression and DNA methylation levels. We found that GBM patients had a higher mutation frequency and SCNVs than LGG patients. Differential mRNAs and lncRNAs between GBM and LGG were identified and a differential mRNA–lncRNA network was constructed and analyzed. We also discovered some differential DNA methylation sites could distinguish between GBM and LGG samples. Finally, we identified some key GBM‐ and LGG‐specific genes featuring multiple‐level molecular alterations. These specific genes participate in diverse functions; moreover, GBM‐specific genes are enriched in the glioma pathway. Overall, our studies explored the distinctions between GMB and LGG using a comprehensive genomics approach that may provide novel insights into studying the mechanism and treatment of brain tumors.

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“…The prognosis is poor with a median survival estimated at 16 months in clinical studies (2–8) and around 12 months in contemporary population-based studies (9). Approximately 5% of patients survive more than 5 years (10). Favorable therapy-independent prognostic factors include lower age and higher neurological performance status at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Overall patient’s survival of glioblastoma associated to molecular markers: a pan-proteomic prospective study

Drelich

Duhamel

Wisztorski

et al. 2020

Preprint

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SUMMARYMolecular heterogeneities are a key feature of glioblastoma (GBM) pathology impeding patient’s stratification and leading to high discrepancies between patients mean survivals. Here, we established a molecular classification of GBM tumors using a pan-proteomic analysis. Then, we identified, from our proteomic data, 2 clusters of biomarkers associated with good or bad patient survival from 46 IDH wild-type GBMs. Three molecular groups have been identified and associated with systemic biology analyses. Group A tumors exhibit neurogenesis characteristics and tumorigenesis. Group B shows a strong immune cell signature and express poor prognosis markers while group C tumors are characterized by an anti-viral signature and tumor growth proteins. 124 proteins were found statistically different based on patient’s survival times, of which 10 are issued from alternative AltORF or non-coding RNA. After statistical analysis, a panel of markers associated to higher survival (PPP1R12A, RPS14, HSPD1 and LASP1) and another panel associated to lower survival (ALCAM, ANXA11, MAOB, IP_652563 and IGHM) has been validated by immunofluorescence. Taken together, our data will guide GBM prognosis and help to improve the current GBM classification by stratifying the patients and may open new opportunities for therapeutic development.SignificanceGlioblastoma are very heterogeneous tumors with median survivals usually inferior to 20 months. We conducted a pan-proteomics analysis of glioblastoma (GBM) in order to stratify GBM based on the molecular contained. Forty-six GBM cases were classified into three groups where proteins are involved in specific pathways i.e. the first group has a neurogenesis signature and is associated with a better prognosis while the second group of patients has an immune profile with a bad prognosis. The third group is more associated to tumorigenesis. We correlated these results with the TCGA data. Finally, we have identified 28 new prognostic markers of GBM and from these 28, a panel of 4 higher and 5 lower survival markers were validated. With these 9 markers in hand, now pathologist can stratify GBM patients and can guide the therapeutic decision.HighlightsA novel stratification of glioblastoma based on mass spectrometry was established.Three groups with different molecular features and survival were identified.This new classification could improve prognostication and may help therapeutic options.8 prognosis markers for oncologist therapeutic decision have been validated.

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Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’‐like features associated with younger age

Cited by 22 publications

References 27 publications

Newly Diagnosed Glioblastoma in Elderly Patients

Newly Diagnosed Glioblastoma in Elderly Patients

Integrating multiple‐level molecular data to infer the distinctions between glioblastoma and lower‐grade glioma

Overall patient’s survival of glioblastoma associated to molecular markers: a pan-proteomic prospective study

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