Annual Report 1997/1998
Annual Report 1997/1998
The goal of the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone is to promote medical genetics at McGill University. Dr. David S. Rosenblatt is the founding director of the Laboratory. The laboratory was established with the help of a million-dollar endowment to McGill and is housed on H5 at the Royal Victoria Hospital. Funding from the Finestone Laboratory is used to advance the academic goals of the Division of Medical Genetics in the McGill University Health Centre (MUHC). This report is available on the Internet (http://www.mcgill.ca/finestone/)
1997-1998 was an excellent year in the area of vitamin B12 metabolism. With his colleague Dr. Roy Gravel in the Medical Research Council of Canada Genetics Group, Dr. Rosenblatt cloned the gene responsible for cblE disease and identified the first mutations in affected patients. The gene was named methionine synthase reductase and was cloned by homology to known genes in lower organisms with the help of computer databases. This type of work would have been impossible a few years ago.
Dr. Patricia Tonin was able to identify six recurrent mutations in the BRCA genes in French Canadian populations. This has led to our clinical service being able to offer a diagnostic panel that is useful in the context of a family history of breast cancer to French Canadian families.
Dr. Guy Rouleau and his team successfully cloned the gene responsible for oculopharygeal muscular dystrophy, a disorder that is very common in Quebec.
After being with the Laboratory from its inception, Estelle Lamothe, M.S. resigned to pursue an alternate career independent of genetics. We appreciate the major efforts she made on behalf of medical genetics, particularly in setting up many of the molecular protocols and tests that we have used over the years. As mentioned above, genetic counselling and molecular testing for women with a family history of breast cancer has been expanded in both the French Canadian and the Ashkenazi Jewish populations. Lidia Kasprzak, M.Sc. and Jennifer Ozaki, M.S. have done excellent work as the genetic counsellors involved with this program. In the spring, Jennifer returned to the United States and Karlene Australie, M.S. joined the clinical team. Maria Galvez has been adept at adapting advances in the research laboratory of Dr. Tonin to meet our clinical needs. With the technical help of Antonia Klitorinos, Dr. Brian Gilfix has established clinical testing for Factor V Leiden and for hemochromatosis. Suzanne Dufrasne, M.Ps. has continued to provide exceptional service to patients interested in the presymptomatic diagnosis of Huntington Disease.
During the year, two scientists from France, Dr. Charles Adjalla and Dr. Abalo Chango worked in our laboratory. Dr. Chango was with us for 8 months and Dr. Adjalla for two years. Dr. Gordon Gowans joined the clinical training program in Medical Genetics at McGill as a fourth year resident after having completed three years of Pediatric training at LSU in New Orleans.
Honours and Awards:
In September 1997, Dr. Hudson was the recipient of the Joe Doupe Young Investigator's Award given by the Canadian Society for Clinical Investigation. Dr. Foulkes was awarded The MGH 175th Anniversary Fellowship and Dr. Tonin was awarded The Stewart Award from the Montreal General Hospital Research Institute.
Specific Accomplishments Submitted by Individual Members:
Dr. Eleanor Elstein: Research has focused on genetic determinants of cardiovascular disease. Over the past year Dr. Elstein identified an association between specific genes of the renin angiotensin system and cardiac allograft vasculopathy. She has also found an association between specific genes involved in endothelial function and certain types of cardiomyopathy. Most recently she has shown that polymorphisms of the ACE gene influence the responsiveness of the endothelium to different ACE inhibitors.
Dr. William Foulkes: A major focus of research in 1997 has been the clinicopathological and survival analysis of patients with hereditary breast cancer. Dr. Foulkes was involved in the first description of linkage in hereditary goitre. In the largest prostate cancer linkage study carried out to date, he showed that there was no strong evidence for linkage of prostate cancer to a putative chromosome 1q locus. Other work involved the role of CDKN2A in multi-site cancer families and ongoing research on the genetics of head and neck cancer. In the past year, Dr. Foulkes also edited a multi authored volume on cancer genetics for Cambridge University Press. This book promises to become a major reference source in the increasingly important clinical field of genetic susceptibility. Dr. Foulkes has been successful in the FRSQ Chercheur Boursier competition.
Dr. Brian Gilfix: APOE and Other Markers Of Dementia: Dr. Gilfix has completed a project at St. Anne's Veterans Hospital (with Dr. L. Briones) on the utility of APOE genotyping in the diagnosis of dementias. This has involved genotyping 194 individuals for polymorphisms in apolipoprotein E and a number of other genes related potentially to dementia. A manuscript on this work has been published and another is in preparation. The same subjects are now being genotyped for a polymorphism in CYP2D6 in collaboration with Dr. J. Nalbantoglu (Montreal Neurological Institute).
Changes In Drug Metabolism In AIDS Patients: In collaboration with Dr. I. Wainer (Montreal General Hospital), Dr. Gilfix has published one paper and recently submitted a second on the changes in drug metabolism that occur in AIDS patients. The metabolic profile of these patients was performed at the Montreal General Hospital, while the identification of the allelic forms of CYP2D6 and NAT2 carried by these patients was performed at the Royal Victoria Hospital.
Risks Factor For Cardiovascular Disease in Chronic Hemodialysis Patients: Dr. Gilfix has received funding to examine the relationship between polymorphisms in a number of genes of the renin-angiotensin system and the occurrence of cardiovascular disease in chronic hemodialysis patients. He is currently assembling and genotyping the patient population.
Dr. Thomas Hudson: The major activity for Dr. Hudson in 1997 was the building of the complex trait mapping group with Dr. Kenneth Morgan at the Montreal General Hospital Research Institute and clinicians at McGill University and the Complexe Hospitalier de la Sagamie. Several projects were in progress in 1998, including the genetics of asthma, lupus, early onset heart disease, NIDDM, and inflammatory bowel disease. Dr. Hudson maintained his assistant-directorship at the Center for Genome Research at the Whitehead Institute/MIT, where he pursued his interests in genome mapping and sequencing, as well as the generation of more than 3,000 SNP markers to be used on a DNA chip for large-scale genotyping studies. Dr. Hudson is a Medical Research Council of Canada Clinical Investigator.
Ken Morgan, PhD: Major research areas are population genetics, pedigree analysis, and genetic modelling. Dr. Morgan has collaborated extensively on the analysis of genetic data in the human and mouse. During the past year, he collaborated with Carmen Sapienza (Temple University, Philadelphia) on the heritability and mapping of chromosome inactivation skewing in humans. He collaborated on mapping two autosomal recessive Mendelian disorders, a spastic ataxia in French Canadians (with Andrea Richter and Serge Melanšon, H˘pital Sainte-Justine; and Thomas Hudson) and a muscular dystrophy in the Hutterite population (with Cheryl Greenberg and Klaus Wrogemann, University of Manitoba; and Mary Fujiwara). He worked with Gustavo Turecki, a physician and graduate student of Guy Rouleau, on testing hypotheses of and modelling the genetics of psychiatric disorders. In a major collaboration with Thomas Hudson on the genetic analysis of complex human diseases including coronary heart disease and non-insulin dependent diabetes in the French Canadian population of the Saguenay-Lac St. Jean region of Quebec, he was responsible for developing the computing infrastructure for and supervising the genetic data analysis.
Dr. David Rosenblatt: The major research accomplishment in 1997 was the successful collaboration with Roy Gravel in the cloning of methionine synthase reductase, the gene responsible for the cblE form of hyperhomocystinemia. This work was possible because of the definition of Dr. Rosenblatt of this disease as a distinct entity and the demonstration that a reducing system associated with methionine synthase was present in human cells. The successful cloning strategies involved a search for homologies between human expressed sequences and sequences involved in the binding of cofactors required for flavodoxin and flavodoxin reductase activities in other organisms. To prove that the putative cDNA was the correct one, mutations were searched for and found in cblE patients. In other work with Dr. Gravel, the changes responsible for the cblG variant form of hyperhomocystinemia were shown to be caused by mutations that resulted in the complete inability to make methionine synthase.
Guy A. Rouleau: Over the past year, Dr. Rouleau's laboratory has been trying to characterize human genes which, when mutant, lead to nervous system dysfunction. Two major themes are currently being addressed. The first relates to a number of hereditary neurodegenerative disorders, where linkage analysis is performed followed by chromosomally based cloning of the defective gene and mutation analysis. Dr. Rouleau is currently investigating amyotrophic lateral sclerosis, spastic paraplegia, spinocerebellar ataxia, epilepsy, oculopharnygeal muscular dystrophy, manic depressive illness and schizophrenia. The second theme includes inherited predispositions to central nervous system cancer. The most important disorder is neurofibromatosis type 2. Attempts are being made define the molecular events underlying carcinogenesis in the brain. The approach involves linkage analysis, reverse genetics, somatic cell genetics, physical mapping of human chromosomes, cDNA cloning and characterization, mutation analysis and cell biology. As mentioned above, the major accomplishment of this past year has been the successful cloning of the gene for oculopharyngeal muscular dystrophy. Dr. Rouleau is a Medical Research Council of Canada Scholar.
Patricia Tonin, PhD: There are two principal areas of research conducted in Dr. Tonin's laboratory. The first involves the identification of genetic factors that are implicated in the development and/or progression of human epithelial ovarian cancer. The second involves the study of genetic factors that predispose to hereditary forms of breast cancer.
Ovarian cancer: Knowledge of the molecular events associated with the development and progression of epithelial ovarian cancer has been limited by the lack of a suitable model system. Also, since the disease is often diagnosed at a late stage when numerous complex chromosomal changes have already taken place, the early molecular events remain largely unknown. Deletions of chromosome 3p and 17q (distinct from the BRCA1 locus) are frequent events in ovarian tumours of epithelial origin. Dr. Tonin's group has shown deletions in low grade, early stage tumours and have hypothesized that these chromosomal regions harbour tumour suppressor genes whose function is lost early in the development and/or progression of ovarian cancer. The goals of an NCIC and MRC funded project, is to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. This past year Dr. Tonin's laboratory has defined three minimal regions of deletions on chromosome 3p that contain putative tumour suppressor genes (Oncogene, In press). She is now in the process of defining the minimal regions of overlap and examining candidate genes. In parallel she has used the approach of differential display technology to identify genes which encode transcripts that are differentially expressed to characterize the pattern of expression in various subtypes of epithelial ovarian cancer. This project done in collaboration with Dr. Tom Hudson utilizes "chip technology" to rapidly identify differentially expressed genes. Pilot studies have been performed using normal epithelial ovarian cells and four spontaneously immortalized ovarian cancer cell lines. A preliminary analysis has revealed that over expressed genes correlate with genes that are known to be amplified in ovarian cancer. The eventual goal of this particular project will be to identify "molecular markers" of ovarian cancer to improve methods of early detection and prognosis of ovarian cancer.
Breast cancer: Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers. With the identification of two predisposing susceptibility genes, BRCA1 and BRCA2, studies are now in progress to focus on: (1) the continued identification of recurrent mutations in specific populations which will lead to improved strategies for mutation detection (e.g. French-Canadian population); (2) correlation of carrier status and various host (reproductive, etc) and environmental factors (e.g. smoking); (3) identification of other susceptibility genes (BRCAX?); and (4) correlating carrier status and various prognostic indicators (e.g. estrogen and progesterone status) to better understand the biology of BRCA1 and BRCA2. To date Dr. Tonin has identified eight BRCA1 and BRCA2 mutations in the French Canadian population, where six mutations have been found to recur more than once in this population. The six recurrent mutations account for a significant proportion of breast and ovarian cancer families and thus can be used to facilitate mutation detection in this population.
David Watkins, PhD: Last year Dr. Watkins completed studies demonstrating that the acquired genetic change in a human melanoma cell line (MeWoLC1) that results in its inability to proliferate in medium in which the amino acid methionine is replaced by its precursor homocysteine, affects the same gene that is defective in patients with cblC, an inborn error of metabolism of vitamin B12. Similar changes were not found in a panel of 13 additional methionine-dependent tumour cell lines.
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