Faculty Bibliography

BACKGROUND:Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known. METHODS:We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test. RESULTS:We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for EP300 that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of EP300 is prognostic, predicting survival independent of age at diagnosis and tumor grade. CONCLUSIONS:We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.

Diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes, and diagnosis is largely based on histologic appearance. Tumor classification according to cell type and grade provides some prognostic information. However, significant clinical and biologic heterogeneity exists in glioma, even after accounting for known clinicopathologic variables. Significant advances in knowledge of the molecular genetics of brain tumors have occurred in the past decade, largely because of the availability of high-throughput profiling techniques, including new sequencing methodologies and multidimensional profiling by The Cancer Genome Atlas project. The large amount of data generated from these efforts has enabled the identification of prognostic and predictive factors and helped to identify pathways driving tumor growth. Implementing these signatures into the clinic to personalize therapy presents a new challenge. Identification of relevant biomarkers, especially when coupled with clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment for patients with glioma.

MOTIVATION/BACKGROUND:We propose a Bayesian ensemble method for survival prediction in high-dimensional gene expression data. We specify a fully Bayesian hierarchical approach based on an ensemble 'sum-of-trees' model and illustrate our method using three popular survival models. Our non-parametric method incorporates both additive and interaction effects between genes, which results in high predictive accuracy compared with other methods. In addition, our method provides model-free variable selection of important prognostic markers based on controlling the false discovery rates; thus providing a unified procedure to select relevant genes and predict survivor functions. RESULTS:We assess the performance of our method several simulated and real microarray datasets. We show that our method selects genes potentially related to the development of the disease as well as yields predictive performance that is very competitive to many other existing methods. AVAILABILITY/BACKGROUND:http://works.bepress.com/veera/1/.

Primary brain tumors are a heterogeneous group of malignancies with highly variable outcomes, and diagnosis is largely based on the histological appearance of the tumors. However, the diversity of primary brain tumors has made prognostic determinations based purely on clinicopathologic variables difficult. There is an increasing body of data suggesting a significant amount of molecular diversity accounts for the heterogeneity of clinical observations, such as response to treatment and time to progression. The last decade has witnessed an explosive advance in our knowledge of the molecular genetics of brain tumors, due in large part to the availability of high-throughput profiling techniques and to the completion of the human genome sequencing project. The large amount of data generated by these efforts has enabled the identification of prognostic and predictive factors and helping to identify pathways which are driving tumor growth. Identification of biomarkers will enable better patient stratification and individualization of treatment.

The diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes and diagnosis is largely based on the histological appearance of the tumors. Tumor classification according to cello type and grade provides some prognostic information. However, the diversity of gliomas, within tumor type and grade categories, has made prognostic determinations based purely on clinicopathologic variables difficult. There is an increasing body of data suggesting a significant amount of molecular diversity accounts for the heterogeneity of clinical observations, such as response to treatment and time to progression. The last decade has witnessed an explosive advance in our knowledge of the molecular genetics of brain tumors, due in large part to the availability of high-throughput profiling techniques, including new sequencing methodologies as well as multidimensional profiling by the Cancer Genome Atlas project. The large amount of data generated by these efforts has enabled the identification of prognostic and predictive factors and helping to identify pathways that are driving tumor growth. Identification of biomarkers, especially when coupled to clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment.

We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.