Annual Report 1995/1996

Annual Report
Highlights: Research
Clinical Activities
Specific Achievements of Individual Members
Honours and Awards
Future Prospects

Annual Report 1995/1996

The goal of the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone is to promote medical genetics at McGill. The laboratory was established with the help of a $1,000,000 gift to McGill University and is housed at the Royal Victoria Hospital. Dr. David S. Rosenblatt is Director of the laboratory and Director of the Division of Medical Genetics at both the Royal Victoria Hospital (RVH) and the Montreal General Hospital (MGH).

The University Division of Medical Genetics in the Department of Medicine at McGill operates at the Royal Victoria Hospital (RVH), at the Montreal General Hospital (MGH) and at the Jewish General Hospital (JGH). The units at the RVH and MGH, under the direction of Dr. David Rosenblatt operate as an integrated entity providing clinical services to the two hospitals. The primary foci at the RVH and MGH is in cancer genetics, neurogenetics, cardiogenetics, genetic epidemiology, and molecular diagnostics. The unit at the JGH, under the direction of Dr. Leonard Pinsky focuses mainly, but not exclusively, in the area of prenatal diagnosis and reproductive counselling. It also has activities in adult-onset genetic disease and the JGH is a world reference centre for androgen insensitivity disorders. The present report discusses only activities at the RVH and MGH.

The Divisions of Medical Genetics at the RVH and MGH have submitted a phase I clinical integration proposal to the Department of Medicine in view of progress towards the formation of the McGill University Health Sciences Centre. This proposal is attached to the present report as Appendix I. Documentation of clinical and laboratory activities can be found in this proposal.

Highlights: Research

1995-1996 was another year of significant accomplishments in the area of research. Dr. Steven Narod and Dr. Patricia Tonin played an important role in the successful isolation of a second gene for hereditary breast cancer (BRCA2). This follows on their role last year in the discovery of the first gene involved in hereditary breast and ovarian cancer (BRCA1). In addition they found that two mutations in the BRCA1 gene are commonly found in women in hereditary cancer families who come from an Ashkenazi Jewish background. Methods for detecting the common mutations were transferred to the molecular diagnostic laboratory. This has made it possible to offer specific genetic testing to women in families who carry these mutations. The close integration of research and clinical activities has allowed for the rapid integration of advances in the area of molecular genetics into clinical practice.

Last year, Dr. Rima Rozen of the MRC Genetics Group at McGill was successful in cloning the gene for methylenetetrahydrofolate reductase. Deficiency of this enzyme is the most common inborn error of folate metabolism. Dr. Rosenblatt has accumulated cultured cells on many of the known patients with this disease from around the world. This area of study became even more fascinating with the discovery by Dr. Rozen that a single amino acid substitution in the gene may change the thermal properties of the enzyme and that this change may be associated with a predisposition to heart disease and stroke. This change is associated with an elevation in the level of homocysteine in the blood. Studies in 1995 determined that the effect of this common polymorphism on homocysteine levels may interact with the nutritional status for the vitamin folic acid. This is another indication of the importance of the combined effect of genetics and environment. The role of homocysteine as a risk factor for a diverse variety of medical disorders including vascular and heart disease and neural tube defects continues to be a major focus of our research.

In the fall of 1995, Dr. Steven Narod left McGill to become Chair of Breast Cancer Research at Women's College Hospital at the University of Toronto. Dr. Narod was instrumental in making the Division of Medical Genetics a world class centre in the area of hereditary cancer. Due to his efforts, Dr. Patricia Tonin and Dr. William Foulkes have received exceptional postgraduate training and are in an excellent position to maintain the momentum which has been established. We wish Dr. Narod success in his new position in Toronto.

Clinical Activities:

Genetic counsellors are proving to be in both great demand and highly mobile. Both Gordon Glendon, and Chia Chia Sun moved to Toronto where they continue to be involved in cancer genetics. Lidia Kasprzak, a new graduate of the McGill genetic counselling program was hired as a genetic counsellor. Corrine Serruya and Suzanne Dufrasne have continued to provide excellent care to our patients. In addition to its other activities, the Division co-ordinates predictive testing for Huntington Disease and in 1995 there were 13 individuals in the program. With Estelle Lamothe still on a leave of absence, the addition of Maria Galvez has been crucial to the successful operation of the laboratory. Both Dr. Brian Gilfix and Dr. Patricia Tonin have continued to play a major role in the success of the clinical laboratory. The scope of clinical activities and the activities of the clinical laboratory is outlined in the clinical integration proposal which is attached to this document as Appendix I.

Specific Achievements of Individual Members:

Dr. Eleanor Elstein maintains an active interest in the genetics of patients with heart disease. In particular, her research focusses on the molecular genetics of cardiomyopathies, diseases that affect the heart muscle. Dr. Elstein is involved in seraching for genes that cause inherited cardiomyopathies using both linkage analysis and a candidate gene approach. She also co-ordinates a genetics clinic for families with these diseases.

Dr. William Foulkes, a physician and Ph.D. from England is currently a Medical Scientist in the Division. He has been continuing his collaborations with colleagues in the UK on ovarian carcinoma. Together they have been continuing to delineate somatic alterations in ovarian cancer (P16, P21, BRCA1, MDM2, TIMP2). With his colleagues in Montreal, he has written commentaries and reviews dealing with risks of ovarian cancer in hereditary cancer syndromes. He has been working on a major prostate cancer project and has collected over 100 families with two or more cases of prostate cancer. DNA has been collected from most of the affected samples and analysis is being performed in Montreal, Quebec City, and London, UK. He has completed a case-control study of head and neck cancer at the Jewish General Hospital and has analysed data from a large case-control study in Brazil. The findings of these studies confirm a role for familial factors in the etiology of head and neck cancer. A case-control study of melanoma has been completed and a study of genes involved in thyroid goitre/cancer is in progress.

Dr. Brian Gilfix completed a project at St. Anne's Hospital with Dr. L. Briones on the utility of ApoE genotyping in the diagnosis of dementias. This has involved genotyping 194 individuals for polymophisms in apolipoprotein E and angiotensin-converting enzyme. The same subjects are currently being genotyped for a polymorphism in CYP2D6 in collaboration with Dr. J. Nalbantaglu of the Montreal Neurological Institute. Studies are planned to examine the relationship between polymorphisms in alpha-1-antitrypsin and alpha-1-chymotrypsin and Alzheimer disease. With Dr. I. Wainer of the MGH studies are planned to look at changes in drug metabolism that occur in AIDS patients. Funding has been received by Dr. Gilfix to look at the relationship between polymorphisms in a number of genes of the renin-angiotensin system and the occurrence of cardiovascular disease in chronic hemodialysis patients.

Ken Morgan, Ph.D. is a genetic epidemiologist who collaborates with many investigators. The identification of disease causing mutations and haplotype analysis in families from different populations allows him to study the diversity and origins of mutations as well as the relationship between genotype and phenotype. Examples of these studies include nephrogenic diabetes insipidus, breast cancer, and spinal muscular atrophy. His role in mapping genes for diseases inherited as simple Mendelian traits or as more complex traits is mostly in the statistical analysis and inference. During last year he participated in the mapping of a late-onset autosomal dominant muscular dystrophy to the long arm of chromosome 14. His laboratory also does the DNA analysis of candidate loci for the study of genetic susceptibility to tuberculosis and he has focussed his work on a large extended kindred that experienced an outbreak of tuberculosis. More basic research in Dr. Morgan's laboratory involves the analysis of non-random X-inactivation.

The laboratory of Dr. David Rosenblatt continues to be the major international referral centre for patients with inborn errors of folate and cobalamin (vitamin B12) metabolism. In 1995, cell lines from 79 patients were sent for diagnostic studies and a specific diagnosis was made in 34 patients. The mutations underlying the genetic heterogeneity in mut methylmalonic aciduria were further characterized and a number of novel mutations have been found. A mutation has been found in both an African and several African-American patients with methylmalonic aciduria. As mentioned above, elevated homocysteine levels are being increasingly recognized as a risk factor for vascular disease and malformations. Since the inborn errors of vitamin B12 and folate metabolism result in elevated homocysteine, they are excellent model systems for genetic susceptibilty to these important medical problems.

The laboratory of Guy Rouleau, M.D., Ph.D. is involved in the molecular analysis of disorders of the human nervous system. Two major themes are being addressed. The first represents a number of hereditary neurodegenerative diseases in which the goal is to perform linkage analysis followed by cloning of the defective gene and mutation analysis. Diseases under investigation include peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN), amyotrophic lateral sclerosis, spastic paraplegia, spinocerebellar ataxia, epilepsy, oculopharyngeal muscular dystrophy (OPMD), hidrotic ectodermal dysplasia (HED), manic depressive illness and schizophrenia. OPMD is the most common muscular dystrophy in Quebec with a frequency of 1/1000. This autosomal dominant disease was mapped to chromosome 14q and it was shown that one haplotype accounts for all cases of French Canadian descent. ACCN, an autosomal recessive disease which leads to lifelong diability and premature death, has been mapped to chromosome 15q. The gene carrier rate in the Lac St.-Jean/Saguenay region of Quebec is thought to be 1/23. HED is an autosomal dominant disease affecting skin and nails that is particularly common in southern Quebec. Dr. Rouleau's group has mapped the disease gene to chromosome 13q and have shown that all affected individuals share a common haplotype. The second theme of Dr. Rouleau's laboratory includes the inherited predisposition to central nervous system cancer. Dr. Rouleau's laboratory has successfully cloned the gene for neurofibromatosis II (NF2) and has identified many of the mutations responsible for this disease.

Patricia Tonin, Ph.D. has two major themes in her laboratory. The first is the indentification of genetic factors that are implicated in the development and progression of ovarian cancer, and the second involves the study of genetic factors that predispose to the hereditary forms of breast cancer. In the past year her laboratory has begun to define the areas of chromosomes 3p and 17q that are commonly deleted in ovarian cancer. These studies make use of a panel of greater than 100 tumour and matched control samples and entail the use of highly polymorphic markers and PCR technology. She has shown that deletions in low grade, early stage tumours and therefore hypothesize that the chromosomal regions being studied harbour tumour suppressor genes whose function is lost early in the development and/or progression of ovarian cancer.

As mentioned above in the hightlights of the year, Patricia Tonin and her colleagues have played a major role in working out the importance of BRCA1 in hereditary breast cancer. In a follow-up to a study identifying recurrent BRCA1 mutations, they showed that at-risk individuals of Ashekenazi Jewish descent harbour an identical BRCA1 mutation (185delAG). This discovery has allowed rapid transfer of molecular testing in this community to the clinical laboratory of the Division of Medical Genetics. They also have shown that the majority of families with early-onset (premenopausal) breast cancer and at least two cases of ovarian cancer are attributable to BRCA1. BRCA1 has thus been shown to be genetically heterogeneous and points to the presence of other predisposing genetic factors. In other studies they have completed a transcription map of the HSD17B locus which is adjacent to the BRCA1 locus. They have shown the loss of the normal allele in tumours of the breast and ovary from individuals with germline BRCA1 mutations supporting the hypothesis that BRCA1 is a tumour supressor gene.

Last year the location of second breast cancer susceptibility gene, called BRCA2, was reported. Dr. Tonin established linkage to the BRCA2 locus on chromosome 13q12-13 in a large multisite cancer family of French-Canadian descent. The interesting clinical features of this family that set it apart from the breast-ovarian cancer syndrome are: the presence of male breast cancers, the absence of gynecological cancers (such as ovarian cancer), and cancers at other sites, particularly cancer of the pancreas. The most significant finding with respect to BRCA2 was the reporting of the identification of this gene. This effort was part of an international collaborative study involving investigators from the McGill group in Canada along with groups in the United States and Europe. The McGill group provided data from linkage analysis of genetic recombinants for the purposes of further refining the location of BRCA2 on chromosome 13q12-13. In addition, they provided genomic DNA from index cases representing 60 unrelated families with site-specific breast cancer that were ascertained in Canada for the purpose of screening candidate BRCA2 cDNAs. Indeed, mutation analysis from two families were included in the report.

David Watkins, has funding from the National Cancer Institute of Canada to study cobalamin metabolism and methionine auxotrophy in tumour cell lines. He has demonstrated that cultured melanoma cells have a defect in vitamin B12 metabolism that is also seen in cells from patients with combined methylmalonic aciduria and homocystinuria due to cblC. He plans to use functional complementation with a cDNA library cloned into a shuttle vector to identify and clone cDNA that can correct the methionine auxotrophy seen in these melanoma cells.

Honours and Awards:

Dr. David Rosenblatt is currently President of the US-based Society for Inherited Metabolic Disorders (SIMD) and is Past President of the Canadian Society for Clinical Investigation (CSCI). He chairs the Clinical Investigation Committee of the Alberta Heritage Foundation served in 1995 on the MRC Genetics Committee. Dr. Rosenblatt is currently Acting Editor of Clinical and Investigative Medicine and Chairman of the RVH Research Institute and Vice President, Research of the RVH.

Dr. Guy Rouleau is an MRC Scholar, and Dr. Patricia Tonin is an MRC/CRS Scholars. Dr. D. Watkins and Dr. W. Foulkes have received awards from the MGH Research Institute.


Dr. R. Sasi was the only candidate to remain as a full time trainee in the CCMG program in molecular genetics. A source of funding for clinical training for Ph.D. candidates must be found in order for this program to maintain viability. Dr. Rosenblatt is Director of the Training Program in the Department of Human Genetics. The two residents, Dr. Laura Arbour and Dr. Gail Graham are both training because of the existence of Canadian transfer slots. Dr. Arbour has successfully completed her training and will be joining the staff of the Montreal Children's Hospital in July 1996. Medical Genetics has been recognized as a specialty by the College of Physicians of Quebec. Eventually Quebec students will be able to obtain training cards to enter Medical Genetics at the Resident I level.

Future Prospects:

The Finestone Laboratory looks with great anticipation at the prospect of the McGill University Health Centre. We remain extremely strong in both research and clinical areas, but are somewhat hampered by our dispersement, and lack of infrastructure. The creation of the Department of Human Genetics at McGill, the recognition of Medical Genetics by the College of Physicians, and the creation of the McGill University Health Centre, all auger well for the future of medical genetics at McGill. We look forward to the implementation of the appended proposal for clinical integration.

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1996 PMNowacki Ent
for Finestone Laboratory