Dataset Information

Distinct genomic aberrations between low-grade and high-grade gliomas of Chinese patients.

ABSTRACT:

Background

Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade.

Methods

We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina's Beadchip and validated the results using real-time qPCR.

Results

AT THE CYTOBAND LEVEL, WE DISCOVERED: (1) unique losses in LGG on 5q, 8p and 11q, and in HGG on 6q, 11p, 13q and 19q; (2) unique gains in the LGG on 1p and in HGG at 5p, 7p, 7q and 20q; and (3) cnLOH in HGG only on 3q, 8q, 10p, 14q, 15q, 17p, 17q, 18q and 21q. Subsequently, we confirmed well-characterized oncogenes among tumor-related loci (such as EGFR and KIT) and detected novel genes that gained chromosome sequences (such as AASS, HYAL4, NDUFA5 and SPAM1) in both LGG and HGG. In addition, we found gains, losses, and cnLOH in several genes, including VN1R2, VN1R4, and ZNF677, in multiple samples. Mapping grade-associated pathways and their related gene ontology (GO) terms, we classified LGG-associated functions as "arachidonic acid metabolism", "DNA binding" and "regulation of DNA-dependent transcription" and the HGG-associated as "neuroactive ligand-receptor interaction", "neuronal cell body" and "defense response to bacterium".

Conclusion

LGG and HGG appear to have different molecular signatures in genomic variations and our results provide invaluable information for the diagnosis and treatment of gliomas in patients with variable duration or diverse tumor differentiation.

SUBMITTER: Li Y

PROVIDER: S-EPMC3579804 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Distinct genomic aberrations between low-grade and high-grade gliomas of Chinese patients.

Li Yunbo Y Wang Dapeng D Wang Lei L Yu Jinhai J Du Danhua D Chen Ye Y Gao Peng P Wang Duen-Mei DM Yu Jun J Zhang Feng F Fu Shuanglin S

PloS one 20130222 2

<h4>Background</h4>Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade.<h4>Methods</h4>We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina's Beadchip and validated the results using real-time ...[more]

PMID: 23451178

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Project description:BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Dataset Information

Distinct genomic aberrations between low-grade and high-grade gliomas of Chinese patients.

Background

Methods

Results

Conclusion

Publications

Distinct genomic aberrations between low-grade and high-grade gliomas of Chinese patients.

Similar Datasets

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