A Network Model of a Cooperative Genetic Landscape in Brain Tumors

Bredel, Markus; Scholtens, Denise M.; Harsh, Griffith R.; Bredel, Claudia; Chandler, James P.; Renfrow, Jaclyn J.; Yadav, Ajay; Vogel, Hannes; Scheck, Adrienne C.; Tibshirani, Robert; Šikić, Branimir I.

doi:10.1001/jama.2009.997

Cited by 171 publications

(136 citation statements)

References 48 publications

(53 reference statements)

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…However, the cellular heterogeneity of clinical samples and the genetic diversity of cancer genomes limit the translation of genomics for improved patient care. A common approach for identifying clinically relevant cancer genome aberrations is to characterize lesions, including any loss or any gain for each chromosome occurring at rates that are statistically significant in samples of interest (2,(37)(38)(39)(40)(41). Single-copy losses and gains occur as part of the random events associated with genomic instability present in tumor genomes.…”

Section: Discussionmentioning

confidence: 99%

Advancing a clinically relevant perspective of the clonal nature of cancer

Ruiz

Lenkiewicz

Evers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

100

102

View full text Add to dashboard Cite

Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing. The results produced high-definition genomic profiles of clonal populations from 40 pancreatic adenocarcinomas and a set of prostate adenocarcinomas, including serial biopsies from a patient who progressed to androgen-independent metastatic disease. The genomes of clonal populations were found to have patient-specific aberrations of clinical relevance. Furthermore, we identified genomic aberrations specific to therapeutically responsive and resistant clones arising during the evolution of androgen-independent metastatic prostate adenocarcinoma. We also distinguished divergent clonal populations within single biopsies and mapped aberrations in multiple aneuploid populations arising in primary and metastatic pancreatic adenocarcinoma. We propose that our high-definition analyses of the genomes of distinct clonal populations of cancer cells in patients in vivo can help guide diagnoses and tailor approaches to personalized treatment.clonal genomics | pancreatic cancer | prostate cancer

show abstract

Section: Discussionmentioning

confidence: 99%

Advancing a clinically relevant perspective of the clonal nature of cancer

Ruiz

Lenkiewicz

Evers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

100

102

View full text Add to dashboard Cite

show abstract

“…Moreover, a subset of the genes represented in these subtypes is represented in a nine-gene panel shown to predict outcome in glioblastoma, as increased expression of mesenchymal genes such as CHI3L1/YKL-40 and LGALS3 combined with decreased expression of a proneural gene, OLIG2, were associated with typical short-term survival compared with longer-term survivors . Considering that other groups have used alternative methodologies to derive nonoverlapping prognostically significant gene sets (Bredel et al 2009), further work in large, relatively uniform sample sets will be necessary to resolve subtype classification systems and validate multiple prognostic gene sets.…”

Section: Classificationmentioning

confidence: 99%

Emerging insights into the molecular and cellular basis of glioblastoma

et al. 2012

View full text Add to dashboard Cite

Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that “glioblastoma” represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.

show abstract

“…Thus, there is an urgent need to develop novel therapeutic approaches to cure this malignancy. As the molecular mechanisms of gliomas have gradually been clarified, improving chemotherapeutic methods is the key to combination treatment (3,(5)(6)(7)(8)(9)(10)(11). The therapeutic goal of chemotherapy is to trigger tumor-selective cell death.…”

Section: Introductionmentioning

confidence: 99%

LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

et al. 2011

View full text Add to dashboard Cite

Abstract. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of glioblastoma (GBM) cases are refractory to TMZ. Previous studies have revealed that the PI3K/ Akt pathway is activated in an ataxia telangiectasia and Rad3 related-dependent manner in response to TMZ. Thus, we hypothesized that PI3K inhibitors may act as antitumor agents against gliomas and potentiate the cytotoxicity of TMZ. The cytotoxicity of a PI3K inhibitor, LY294002, was examined both alone and in combination with TMZ in human glioma cell lines. Proliferation of tumor cells treated with LY294002 in combination with TMZ was significantly suppressed compared to treatment with either drug used alone. The combination treatment induced a higher apoptosis rate, while reducing the invasive capability of U87 cells. The apoptosis-associated proteins, cleaved-caspase-3 and Bax, were more significantly up-regulated by the combined treatment than by TMZ used alone. In addition, p-Akt and Bcl-2, which can promote TMZ resistance, were markedly decreased by LY294002. These findings suggest that LY294002 enhances the cytotoxicity of TMZ by down-regulation of the PI3K/Akt pathway.

show abstract

A Network Model of a Cooperative Genetic Landscape in Brain Tumors

Cited by 171 publications

References 48 publications

Advancing a clinically relevant perspective of the clonal nature of cancer

Advancing a clinically relevant perspective of the clonal nature of cancer

Emerging insights into the molecular and cellular basis of glioblastoma

LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

Contact Info

Product

Resources

About