DNA methylation profiles of long- and short-term glioblastoma survivors

Shinawi, Thoraia; Hill, Victoria; Krex, Dietmar; Schackert, Gabriele; Gentle, Dean; Morris, Mark R.; Wei, Wenbin; Cruickshank, Garth; Maher, Eamonn R.; Latif, Farida

doi:10.4161/epi.23398

Cited by 114 publications

(104 citation statements)

References 15 publications

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“…As for HOXD8 , HIST1H3E and MAP4K1 , only HOXD8 contributes to distinguishing cluster 1 from the others. As studied in [45], HOXD8 is differentially hypermethylated between short-term survivors and long-term survivors among the GBM patients, which is in agreement with our analysis of survival outcomes for the three clusters.…”

Section: Resultssupporting

confidence: 91%

Integrative and regularized principal component analysis of multiple sources of data

Liu

Shen

Pan

2016

Statistics in Medicine

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Integration of data of disparate types has become increasingly important to enhancing the power for new discoveries by combining complementary strengths of multiple types of data. One application is to uncover tumor subtypes in human cancer research, in which multiple types of genomic data are integrated, including gene expression, DNA copy number and DNA methylation data. In spite of their successes, existing approaches based on joint latent variable models require stringent distributional assumptions and may suffer from unbalanced scales (or units) of different types of data and non-scalability of the corresponding algorithms. In this paper, we propose an alternative based on integrative and regularized principal component analysis, which is distribution-free, computationally efficient, and robust against unbalanced scales. The new method performs dimension reduction simultaneously on multiple types of data, seeking data-adaptive sparsity and scaling. As a result, in addition to feature selection for each type of data, integrative clustering is achieved. Numerically, the proposed method compares favorably against its competitors in terms of accuracy (in identifying hidden clusters), computational efficiency, and robustness against unbalanced scales. In particular, compared to a popular method, the new method was competitive in identifying tumor subtypes associated with distinct patient survival patterns when applied to a combined analysis of DNA copy number, mRNA expression and DNA methylation data in a glioblastoma multiforme study.

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Section: Resultssupporting

confidence: 91%

Integrative and regularized principal component analysis of multiple sources of data

Liu

Shen

Pan

2016

Statistics in Medicine

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“…This is further supported by results from the TCGA consortium and others who have shown that IDH mut and G-CIMP tumors have a much better outcome and lack prototypical genetic alterations of pGBM such as EGFR amplification, CDKN2A deletions, and PTEN loss [2,42,52,55]. Unsurprisingly, a large number of studies have found a higher proportion of IDH mut [21] and G-CIMP tumors [47] among LTS. These data imply that available studies on long-term survival may have been confounded by IDH mutations, and further research is warranted to elucidate the mechanisms contributing to improved survival in primary, IDH wt glioblastoma.…”

Section: Introductionmentioning

confidence: 52%

“…At the same time, studies on CNAs usually detected hallmark lesions of primary GBM among STS and common aberrations of lower grade lesions among LTS [3,4]. This bias extends across all levels of cell biology including epigenetics, which is why methylation screening found G-CIMP tumors to be overrepresented among LTS [47]. Additional proof comes from the reportedly high histopathological misclassification rates [39] in LTS and the high prevalence of IDH mutations among them [21].…”

Section: Discussionmentioning

confidence: 92%

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

et al. 2015

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Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH (wt) long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH (wt) cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup.

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“…Given limitations of tissue availability, we were unable to explore whether the LTS phenotype in our cohort is linked to recently characterized gene expression or DNA methylation signatures (29)(30)(31). The first high-throughput approaches have indeed suggested links between LTS and decreased retinoic acid signaling (32), enhanced immunerelated gene expression (33), or distinct DNA methylation profiles (34), but more studies with larger patient populations seem to be required to decide whether tumor rather than host factors are chiefly responsible for LTS. …”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

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163

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Purpose: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.Experimental Design: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

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DNA methylation profiles of long- and short-term glioblastoma survivors

Cited by 114 publications

References 15 publications

Integrative and regularized principal component analysis of multiple sources of data

Integrative and regularized principal component analysis of multiple sources of data

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

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