TPQCI: A topology potential-based method to quantify functional influence of copy number variations

Copy number variation (CNV) is a major type of chromosomal structural variation that play important roles in many diseases including cancers. Due to genome instability, a large number of CNV events can be detected in diseases such as cancer. Therefore, it is important to identify the functionally important CNVs in diseases, which currently still poses a challenge in genomics. One of the critical steps to solve the problem is to define the influence of CNV. In this paper, we provide a topology potential based method, TPQCI, to quantify this kind of influence by integrating statistics, gene regulatory associations, and biological function information. We used this metric to detect functionally enriched genes on genomic segments with CNV in breast cancer and multiple myeloma and discovered biological functions influenced by CNV. Our results demonstrate that, by using our proposed TPQCI metric, we can detect disease-specific genes that are influenced by CNVs. Source codes of TPQCI are provided in Github (https://github.com/usos/TPQCI)

Deconstructing the carcinogenome: cancer genomics and exposome data generation, analysis, an tool development to further cancer prevention and therapy

The rise in large-scale cancer genomics data collection initiatives has paved the way for extensive research aimed at understanding the biology of human cancer. While the majority of this research is motivated by clinical applications aimed at advancing targeted therapy, cancer prevention initiatives are less emphasized. Many cancers are not attributable to known heritable genetic factors, making environmental exposure a main suspect in driving cancer risk. A major aspect of cancer prevention involves the identification of chemical carcinogens, substances linked to increased cancer susceptibility. Traditional methods for chemical carcinogens testing, including epidemiological studies and rodent bioassays, are expensive to conduct, not scalable to a large number of chemicals, and not capable of detecting specific mechanisms of actions of carcinogenicity. Thus, there exists a dire need for improvement in data generation and computational method development for chemical carcinogenicity testing. Here, we coin the term "carcinogenome" to denote the complete cancer genomic landscape encompassing both its repertoire of environmental chemical exposures, as well as its germ-line and somatic mutations and epi-genetic regulators. To study the carcinogenome, we analyze both the genomic behavior of real human tumors as well as profiles of the exposome, that is, data derived from chemical exposures in human, animal or cell line models. My thesis consists of two distinct projects that, through the generation and innovative analysis of multi-omics data, aim at advancing our understanding of the molecular mechanisms of cancer initiation and progression, and of the role environmental exposure plays in these processes. First, I detail our effort at data generation and method development for characterizing environmental contributions to carcinogenesis using transcriptional profiles of chemical perturbations. Second, I present the tool iEDGE (Integration of Epi-DNA and Gene Expression) and its applications to the integrative analysis of multi-level cancer genomics data from human primary tumors of multiple cancer types. These projects collectively further our understanding of the carcinogenome and will hopefully foster both cancer prevention, through the identification of environmental chemical carcinogens, and cancer therapy, through the discovery of novel cancer gene drivers and therapeutic targets

Molecular heterogeneity of invasive penile cancer

Penile cancer is a rare and mutilating disease. Due to the paucity of basic, molecular and translational work, new treatment options have not been forthcoming and the disease has arguably been neglected, and patients have poor outcomes. This thesis explores the molecular biology of advanced squamous cell penile carcinoma by assessing its genetic and epigenetic aberrations, and transcriptomic changes. For each patient, five tumour regions were profiled in detail and compared with a matched control sample. When compared with other cancers, penile cancer appears to have a high tumour mutational load with high intra-tumour heterogeneity. Evidence for the clonal integration of HPV into the human genome was found. HPV positive samples are associated with APOBEC mutational changes and increased expression of DNMT1 and DNMT3A methyltransferases. TP53 was found to be an early clonal driver in the HPV negative samples, whereas mutations in mTOR or PIK3CA were found to be early clonal drivers in HPV positive samples. Potentially targetable mutations, such as EGFR, were only ever found to be subclonal in this small cohort. Other targetable mutations that were found to be early and shared throughout the primary tumour included DDR2 and cMET. Increased expression of immune checkpoint inhibitory proteins such as CTLA4 were found throughout all samples, providing preliminary evidence that checkpoint blockade could be effective in penile cancer. These findings suggest that penile cancer is a heterogeneous disease with remarkably different genetic and epigenetic profiles for HPV positive and HPV negative disease. These tumours display large amounts of intra-tumour heterogeneity and so may prove difficult to successfully treat with more traditional targeted therapies against tyrosine kinases. However, there is evidence that immune checkpoint blockade may prove to be efficacious in these patients and further work should be undertaken to examine this in more depth