The Human Genome Project identified approximately 25,000 genes in human DNA, which was much less than expected. However, about 60 percent of these genes undergo alternative splicing, in which one gene is assembled from its component pieces in many different ways. This phenomenon enables genes to have incredibly diverse variations that represent hundreds of thousands of functional units. Malachi Griffith is studying how changes in certain genes due to alternative splicing may have an important role in cancer progression and could account for differences in the severity of the disease from one individual to another. Malachi is comparing large sets of data from genes in healthy individuals and cancer patients to determine if differences in gene forms help explain the causes of different cancers. Findings could contribute to improved diagnosis and treatment of cancer.
Research Location: BC Cancer Agency - Vancouver
Identification of novel genetic alterations in Lung Carcinogenesis
Lung cancer is the leading cause of cancer death in North America, with less than 15 percent of people surviving five years after diagnosis. The prognosis is poor because there are no symptoms in the early stages of lung cancer, which often results in the disease going undiagnosed until it is too late for established treatment to be effective. To increase the survival rate, diagnosis and treatment must occur earlier. Cumulative genetic changes are believed to cause cancer. Several genetic alterations have been identified in tumours, but the genes that lead to lung cancer remain unknown. Cathie Garnis is examining genetic changes in pre-malignant tumours to identify genes that play a significant role in lung cancer progression. The results could improve understanding of the biology behind lung cancer, and ultimately help clinicians diagnose the disease earlier and develop more effective treatments.
Computational identification of genetic variation in gene regulatory networks
Our genes encode all the information that makes us human. The recent sequencing of the human genome, completed in 2003, identified all of the approximately 30,000 genes in human DNA. However, each person has variations in their genetic makeup that account for the diversity in their quality of life. A major focus of genetic research is studying the nature of genetic variation. Single nucleotide polymorphisms (SNPs) are variations in DNA sequences that are the most common molecular mechanisms of genetic variation. Studies show SNPs play a role in the development of various diseases, including depression, cancer, lupus and Alzheimer’s. Stephen Montgomery, who was part of the research team at Canada’s Michael Smith Genome Sciences Centre that sequenced the SARS virus, has been designing and building software to aid in identifying SNPs and other sources of genetic variation that regulate gene expression (the process by which genes are transcribed and translated into proteins). His work on further developing these tools and techniques could improve understanding of the molecular causes of genetic variation, which could suggest new therapies for combating diseases.
Natural killer cell lineage commitment
Natural killer (NK) cells are white blood cells that fight infection by killing a variety of virus-infected cells and tumours. NK cells can distinguish normal, healthy cells from unhealthy cells and kill only the latter. It’s also believed that NK cells help eliminate residual tumour cells following bone marrow transplant into leukemia patients. While the function of NK cells has been well-researched, less is known about how these cells develop. All blood cells arise from hematopoietic stem cells through a process called lineage commitment, in which stem cells differentiate into various types of cells. Linnea Veinotte aims to define that process for NK cells. In previous research funded by MSFHR, Linnea discovered that some NK cells express a gene specific to T cells: the T cell receptor gamma gene. Linnea is investigating T cell receptor gamma gene expression in NK cells and how it may help define the developmental pathway of NK cells. The findings could provide insights about how NK cells develop — crucial information given the important role of NK cells in the body’s immune response.
A novel approach to studying DNA copy number variation in schizophrenia and bipolar disorder
Schizophrenia and bipolar disease are severe mental illnesses that affect thinking, mood and behaviour, and cause lifelong disability. Schizophrenia alone costs the Canadian economy about $2.5 billion per year. While the exact causes remain unknown, both disorders are thought to arise from the interaction of genetic defects with environmental factors. Research into these psychotic disorders lags behind advances in other health fields, so new and innovative research strategies are needed. Studies have shown that certain DNA changes can strongly predispose people to psychotic disorders, but the full scope of DNA changes in schizophrenia and bipolar disease has not been explored. Dr. Robert Holt is using new technology called microarray comparative genome hybridization to scan the entire genome of patients with schizophrenia and bipolar disease to detect losses or gains of DNA. The research could contribute to better understanding of the genetic factors that predispose people to schizophrenia and bipolar disorder, lead to diagnostic tests to identify those at risk, and strategies for early intervention to achieve better outcomes.
Identification of genes key to the progression of squamous cell carcinoma of the lung by 3p array comparative genomic hybridization
Lung cancer accounts for the majority of cancer deaths in Canada. Unfortunately, diagnosis typically occurs after lung cancer is well-established, too late for effective treatment. To develop more effective ways of detecting and treating cancer, researchers are studying the genetic makeup of patients, with the goal of identifying and characterizing particular genes that may either suppress or promote the onset and progression of lung cancer. Using an approach that combines laboratory benchwork with bioinformatics techniques (the use of computer tools and databases to analyze large amounts of biological data), Bradley Coe is focusing his work on a specific chromosome, 3p, with which genetic alterations have recently been linked to the development of lung cancer. Identifying genes critical to the disease process will lead to a better overall understanding of lung cancer and may point the way to more targeted diagnostic tests and treatment.
Identification of gene regulatory changes involved in cancer progression by gene expression studies and bioinformatic analyses
Obi Griffith was part of a team at the BC Cancer Agency’s Michael Smith Genome Sciences Centre, that cracked the genetic code for Severe Acute Respiratory Syndrome (SARS) in April 2003. In his MSFHR-funded research, Obi is examining how changes in the regulatory sequences of DNA may lead to cancer. By comparing the activation patterns of clusters of genes in normal and cancerous tissue, Obi is working to identify genes that undergo a change in regulation leading to cancer. Once these cancer-causing mutations are identified, he will investigate the biochemical mechanisms responsible for these regulatory changes. Learning more about specific gene regulation changes that lead to cancer may lead to new ways to diagnose, predict and treat cancer using gene-based therapies.
Role of DNA methylation and histone modification in the transcriptional regulation of mouse Ly49 genes
Natural killer (NK) cells are a subset of white blood cells and are part of the innate immune system. Their activation, unlike that of the adaptive immune system, does not require exposure to a foreign substance. NK cells are considered a first line of immune defense in the body, as they can recognize and destroy altered cells such as virus-infected or tumour cells. On the surface of normal cells there are receptor molecules called MHC class-I, which are recognized by receptors on the surface of NK cells. The interaction of NK receptors and MHC class-I prevents NK cells from destroying normal cells. NK cells are able to destroy virus-infected cells and cancer cells because in these cells, MHC class-I molecules are often not expressed (shut off). In both human and mouse, the repertoire of receptors varies among different NK cells. To better understand how NK genes are regulated, Arefeh Rouhi is studying the mechanisms that control these variations among NK cells. Ultimately, this knowledge may lead to ways to use the body’s own immune system to protect against infections and malignancy.
Dose corrections for inhomogeneities in small field intensity modulated x-ray radiation therapy
Alanah Bergman’s research focuses on the use of high energy x-ray radiation in cancer treatment. Radiation fields are shaped to deliver high doses that conform closely to the shape of the tumour being targeted. A new technique called Intensity Modulated Radiation Therapy (IMRT) uses a collimator to fine-tune the shape and intensity of the radiation field. But it is difficult to accurately calculate the dose for small fields, especially when inhomogeneous tissue — such as lung, air or bone — is included in the treatment area. Alanah Bergman is investigating methods for improving dose calculations for x-ray radiation treatment. She will quantify errors in dose calculations and modify the calculations to improve their accuracy. Results from the study could provide radiation oncologists with better tools for making treatment decisions and ultimately benefit patients receiving radiation therapy for cancer, particularly cancers of the head/neck, lung and breast.
Molecular mechanism of genomic instability and telomere shortening in Dog-1 mutants
BRCA1 is a breast cancer susceptibility gene found in more than 80 per cent of families in which six or more family members have had breast cancer. A protein that interacts with this gene is very similar to a specialized enzyme, called a helicase, in the worm. Iris Cheung and her colleagues have demonstrated that the helicase is required to prevent the loss of DNA that is rich in guanine (one of the four components of DNA). Without the enzyme, DNA is lost in multiple sites in the worm genome, resulting in genetic instability and opening the door for normal cells to develop into tumour cells. Iris Cheung is researching how the prevention of genetic mutations in the worm may provide clues to how mutations arise and are prevented in the gene known to cause breast cancer. Findings may help improve researchers’ understanding of the development and properties of breast cancer, and potentially the development of new therapies.