Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Metabolomic Biomarkers for Colorectal Cancer

Colorectal cancer (CRC) is the second most common cancer in the North America. It is also a huge burden for society. Remarkable efforts have been and are being made to improve CRC diagnosis, to enhance the effectiveness of treatments, and to eventually improve the outcome of these patients. Metabolomic profiling, as a method for describing metabolic state and alterations in the molecular constituents and capable of yielding unique and invaluable information about tumor biology, has been employed. Using a range of spectroscopy and mass spectrometry techniques, we have sought to characterize the changes in the serum metabolome that appear as a result of malignant and pre-malignant lesions in the colon and rectum. In Chapter 2, Application of gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy for staging CRC is described. Chapter 3 describes a larger study of 320 CRC and 31 colorectal adenoma cases as well as their matching controls by GC-MS, which led to the identification of validated metabolomic signature for identification of CRC and a proposed signature for identification of colorectal adenoma. In chapter 4, an effort for quantitative profiling of 62 CRC cases and 31 colorectal adenomas and their matching controls by tandem mass spectrometry is illustrated, and a validated quantitative signature for diagnosis of CRC is reported. Chapter 5 is dedicated to studying the prognostic value of metabolomic profiling in colorectal liver metastatic patients, and a novel workflow for estimation of recurrence risk using high-dimensional data is proposed. Challenges and pitfalls confronted in different steps of the project were addressed when possible by the use of available methods. Where no reliable method was available, we made an effort to develop one. This thesis, therefore, is focused on the metabolomic characterization of CRC and the adaptation of this knowledge for the development of clinically valuable biomarkers

From Genotype to Functional Phenotype: Unraveling the Metabolomic Features of Colorectal Cancer

Much effort in recent years has been expended in defining the genomic and epigenetic alterations that characterize colorectal adenocarcinoma and its subtypes. However, little is known about the functional ramifications related to various subtypes. Metabolomics, the study of small molecule intermediates in disease, provides a snapshot of the functional phenotype of colorectal cancer. Data, thus far, have characterized some of the metabolic perturbations that accompany colorectal cancer. However, further studies will be required to identify biologically meaningful metabolic subsets, including those corresponding to specific genetic aberrations. Moreover, further studies are necessary to distinguish changes due to tumor and the host response to tumor

A Framework for Development of Useful Metabolomic Biomarkers and Their Effective Knowledge Translation

Despite the significant advantages of metabolomic biomarkers, no diagnostic tests based on metabolomics have been introduced to clinical use. There are many reasons for this, centered around substantial obstacles in developing clinically useful metabolomic biomarkers. Most significant is the need for interdisciplinary teams with expertise in metabolomics, analysis of complex clinical and metabolomic data, and clinical care. Importantly, the clinical need must precede biomarker discovery, and the experimental design for discovery and validation must reflect the purpose of the biomarker. Standard operating procedures for procuring and handling samples must be developed from the beginning, to ensure experimental integrity. Assay design is another challenge, as there is not much precedent informing this. Another obstacle is that it is not yet clear how to protect any intellectual property related to metabolomic biomarkers. Viewing a metabolomic biomarker as a natural phenomenon would inhibit patent protection and potentially stifle commercial interest. However, demonstrating that a metabolomic biomarker is actually a derivative of a natural phenomenon that requires innovation would enhance investment in this field. Finally, effective knowledge translation strategies must be implemented, which will require engagement with end users (clinicians and lab physicians), patient advocate groups, policy makers, and payer organizations. Addressing each of these issues comprises the framework for introducing a metabolomic biomarker to practice

A creative method to tune Fe–O interaction in ferrites

To be able to regulate the anionic oxygen position in ferrites, an original compositing method is developed by introducing a porous p-type phase in the n-type matrix of ferrite spinel semiconductors. A result of this method is the synergetic effect of the enhanced mass and charge transport that impacted the morphology and anionic oxygen position within the MgFe2O4 structure. Our hypothesis is that fine tuning of the anionic oxygen position in ferrites allows us to regulate their physicochemical properties significantly, with the implications for diverse applications. The electron exchange interaction (J) between O-centered and octahedral-occupying iron (Fe)-centered orbitals affected both the electrical and magnetic properties of the matrix significantly, supporting our hypothesis. The three-dimensional variable range electron hopping is one such effect.</p