2011 Lap-Chee Tsui Publication Award Recipients

The Institute of Genetics of the Canadian Institutes of Health Research (CIHR-IG) is pleased to announce the 2011 recipients of the Lap-Chee Tsui Publication Award, a prize for exceptional trainee-conducted research within the mandate of the Institute of Genetics. CIHR-IG established the award to honour one of Canada's greatest researchers, Lap-Chee Tsui, whose discovery of the gene for cystic fibrosis was a milestone in human genetic disease research.

The 2011 Award Recipients for the Lap-Chee Tsui Publication Award are:

In biomedical research:

In clinical, health services, population health, or genetic ethical, legal and social issues research:

A total of 27 nominations were received, 23 in biomedical research and 4 in clinical, health services, population health, and genetic ethical, legal and social issues research. We would like to take this opportunity to thank all the nominators for their interest in this program and all the nominees for their outstanding contribution to genetic research.

For details regarding the next competition round please visit the CIHR-IG website.

Sincerely,

Paul Lasko, PhD
Scientific Director
Institute of Genetics, CIHR

Lay Summaries

Evolution of human bcr-abl lymphoblastic leukemia-initiating cells

An increasing body of evidence indicates that leukemia relapse is due to the outgrowth rare genetic subclones present at diagnosis. Failure to eradicate minor clones by conventional therapeutic approaches suggests that response to therapy intrinsically varies amongst individual subclones. Therefore, a basic understanding of the evolution of distinct genetic clones during tumor progression, and elucidating the mechanisms that render particular clones resistant to therapy is necessary to improve patient outcome. This study now provides the unique capacity to segregate and examine the relationship between subclones from patients at diagnosis. Additionally, this study provides a means to measure therapeutic efficacy on single subclones in patients who received xenografts to elucidate the genetic determinants of resistance. Effective treatment will only be achieved if all tumor subclones present at diagnosis can be extinguished.

An Expanded Palette of Genetically Encoded Ca2+ Indicators

Visualizing biochemical events inside cells by real-time fluorescence imaging is crucial to understanding the molecular basis of cellular physiology in healthy and diseased states. The visualization of calcium ions in live cells by fluorescent calcium indicators has provided numerous insights into the signaling pathways mediated by this ubiquitous second messenger. For this type of experiment, indicators that are made from protein are particularly useful, since they can be easily introduced in the form of DNA, and their concentration and subcellular localization can be easily controlled. A genetically encoded calcium ion indicator based on the green fluorescent protein from jellyfish has been available for a decade. However, there has been very little progress in making better indicators or new colors of indicator. In this work, we developed a method to engineer very effective new calcium indicators based on fluorescent proteins. The trick to this method was to target them to outside of bacteria where the fluorescence of the indicators could be experimentally manipulated. In this way, we were able to screen very large libraries of potential calcium ion indicators to find the rare clones with improved performance. This allowed us to perform a type of artificial evolution to improve the indicators and make new colors. Specifically, we developed new blue, red, and improved green indicators, as well as two different types of indicator that change their fluorescence color in the presence of calcium ions. These indicators have opened the door to multicolor calcium imaging in single cells, tissues and model animals.

Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study

Cancer predisposition syndromes are genetic conditions which place individuals at increased risk of developing cancer. Li Fraumeni syndrome is a prototypic predisposition syndrome, characterized by multiple, early-onset malignant tumours including cancers of the breast, brain, muscles, bones and other organs. Given that individuals with Li Fraumeni syndrome face an extraordinarily high (up to 90%) lifetime risk of developing cancer, we sought to develop a comprehensive surveillance protocol for these patients. Using a combination of readily available and non-invasive bloodwork and imaging techniques, we were able to detect cancers at an early stage and/or small size, before patients manifested any symptoms. Cancers were identified before progression to a more advanced stage, and this early detection often spared patients from exposure to potentially toxic therapies including chemotherapy and radiation. Patients undergoing surveillance had improved survival rates compared to those patients whose cancers were detected after they had developed symptoms. This work is the first to show benefit from the application of a surveillance protocol in patients with Li Fraumeni syndrome, and therefore lends support for genetic screening of at-risk pediatric and adult patients. Our study offers physicians a management approach for patients with Li Fraumeni syndrome, which can be incorporated into the care they deliver in the context of a multidisciplinary team.

Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 Variation and Smoking Behaviors and Lung Cancer Risk

Smokers with variation in the nicotine metabolic gene, CYP2A6, and the nicotinic receptor subunit genes, CHRNA5-CHRNA3-CHRNB4, have a greater risk of smoking more cigarettes, becoming more dependent on nicotine and developing lung cancer according to a study published in the September issue of the Journal of the National Cancer Institute. Furthermore, the genetic risk for lung cancer due to variation in these two genes is highest among lighter smokers consuming twenty or fewer cigarettes per day. Both genes interact with nicotine, as well as carcinogenic nitrosamines, from cigarette smoke and have previously been linked to smoking behaviours and lung cancer in independent studies. This study, which included 417 lung cancer patients and a comparison group of 223 individuals with no cancer, all current or former smokers, is the first to investigate the relative and combined contribution of variation in these genes. CYP2A6 appeared to have a larger influence on how many cigarettes people smoke each day, while CHRNA5-CHRNA3-CHRNB4 had a larger impact on the risk of developing lung cancer. The combined effect of having both the high-risk CYP2A6 and CHRNA5-CHRNA3-CHRNB4 gene variations more than doubled the odds of developing lung cancer, and this increase in risk was in addition to the impact on cigarette consumption. An assessment of lung cancer risk by level of cigarette consumption uncovered greater genetic risk for lung cancer within lighter smokers – important given that people are smoking less than they used to and lighter smokers tend to perceive lower health risks associated with cigarette smoking.

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