Computational Bioinformatics & Bio-imaging Laboratory (CBIL)


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Proteome Characterization Center: A Genoproteomics Pipeline for Cancer Biomarkers

Molecular characterization of human cancers has generated large volumes of genomic data through comprehensive and coordinated efforts such as The Cancer Genome Atlas (TCGA) Project. However, the mechanisms by which alterations of these cancer genes singly or cooperatively transform cells remain poorly understood. The overarching hypothesis of our PCC is that genomic data provides a highly valuable molecular draft toward the identification of genes and pathways that potentially could be useful for discovery of cancer biomarkers. The proteomic characterization of cancer tissues and plasma samples with genomic data represent the key step not only to verify the genomic alterations at the protein level but also allow for the analysis of unique features that are inherent to proteins including post-translational modifications. In addition, these protein features are likely detected in body fluids by direct measurement of these secreted or otherwise leaked proteins or by the body's immune response to the tumor antigens that can be used as surrogate markers for disease detection with minimum invasion.

The main goal of our Biomarker Discovery Unit is to comprehensively characterize tumor and normal biospecimens and identify their protein composition in order to systematically identify and prioritize ovarian cancer-related proteins for advancement to verification. The objectives of our Biomarker Verification Unit is to develop quantitative and multiplex assays that are sensitive, accurate, and reproducible to verify ovarian cancer candidate biomarkers identified and selected by the Biomarker Candidate Selection Subcommittee of the CPTC and to verify them in tissue and plasma for their potential as biomarkers to detect ovarian cancer early and/or to discriminate malignant from benign ovarian tumors. It is expected that the verified proteins from this proposal will provide a repertoire of new biomarkers for future clinical and translational studies to determine their clinical utility. To achieve these goals, we have proposed a proteomic technology pipeline consisting of protein microarray and mass spectrometry-based methods developed or established by our internationally known investigators in our team to characterize proteins from genetic mutations, rearrangements, gene expression, post-translational modifications (phosphorylation, glycosylation, and acetylation) as well as autoantibodies against cancer-specific protein changes. In addition, the proteomics investigators will work with our multidisciplinary team of scientists and clinicians that includes experts in clinical oncology, clinical chemistry, cancer biology, genomics, bioinformatics, biostatistics, experimental design, metrology/standards, technology optimization, assay construction, and project management for the development of biomarkers with specific clinical utilities for ovarian cancer.

We propose six specific aims: 1. Conduct technologically advanced, comprehensive, and rigorous characterization of proteins in biospecimens provided by the CPTC Resource Center in order to identify proteins and modified proteins (proteins from mutated or rearranged genes and post-translational modifications including phosphorylation, glycosylation, and acetylation) in cancer tissues. [Discovery]. 2. Prioritize the candidate proteins for their ability to detect ovarian cancer early and/or to distinguish ovarian cancer from benign pelvic masses using an independent set of tissue specimens from our PCC. Furthermore, plasma from matched PCC samples will be used to identify auto-antibodies that recognize the altered cancer-associated proteins. [Discovery]. 3. Establish systematic, comprehensive data analysis criteria for selection and prioritization of ovarian cancerrelated proteins and their alterations for verification using integrated bioinformatics approaches that incorporate existing knowledge, databases, and literature references in the selection process. [Discovery]. 4. Systematically develop verification assays against protein targets identified and selected by the Biomarker Candidate Selection Subcommittee. [Verification]. 5. Apply the multiplex verification assays in plasma specimens to evaluate the clinical performance of the markers for the early detection of ovarian cancer and/or discrimination of malignant from benign tumors. [Verification] 6. Develop proteomic technologies and bioinformatics tools for biomarker discovery and verification. [Both].




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