Annual Report 2003/2004
Annual Report 2002/2003
Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone
was established to promote the field of medical genetics at
In 2003, the Hess B. and Diane Finestone
Laboratory moved from the fifth floor of the Hersey pavilion of the
Dr. William Foulkes and his collaborators have been involved in DNA and tissue profiling in hereditary breast cancer. The most significant achievement in relation to this project was their clear description of the basal epithelial phenotype of BRCA1-related breast cancer. This has several important implications for the origin, and possibly treatment, of BRCA1-related breast cancer.
Dr. Thomas Hudson and his laboratory
continued its asthma, diabetes and other complex trait mapping projects. Two recent major publications of the
laboratory (published in Science and Nature, with collaborators in
Dr. Kenneth Morgan and his group, in collaboration with Dr. Danielle Malo, by linkage and survival analysis, showed that the gene encoding the toll-like receptor 4 plays a role in resistance to salmonella infection in chickens.
Dr. David Rosenblatt and colleagues published an article in the New England Journal of Medicine, warning that a deficiency of MTHFR (methylenetetrahydrofolate reductase) could be a risk factor for those undergoing anesthesia with nitrous oxide.
Dr. Kenneth Morgan received an Award of
Excellence from the Genetics Society of Canada for life-long contributions to
genetics, teaching and training in
Dr. Mary Ann Thomas has returned from
maternity leave and is completing her RV year of residency and her first year
in the cytogenetics program of the CCMG. Dr. Chantal Morel has completed her
RIV year and her term as our Chief Resident in Medical Genetics. Dr. Teresa Rudkin and Dr. Fatma Bastaki
completed their RIII year and Dr. Nicolas Ah Mew completed his RII year.
Philippe Campeau, who as part of an agreement between Laval and McGill,
completed his RI year in
After more than three years, clinical services for medical genetics within the McGill University Health Centre (MUHC) are still in the process of being restructured. The administration of the MUHC has not yet moved to search for a Program Director for medical genetics. Despite this, we have been able to maintain the excellence of our clinical service, particularly in the area of cancer genetics and in the area of the diagnosis of patients with inborn errors of folate and vitamin B12 metabolism.
Dr. Valerie Désilets is the Director of the prenatal diagnosis
at McGill and as such functions from the Royal Victoria, Montreal
Children’s and Jewish General Hospitals. She has ongoing research
interests in male-mediated developmental toxicity, the isolation of free fetal
DNA from the blood of mothers in order to diagnose genetic disease, the
creation of a data bank for prenatal diagnosis, and the follow-up of newborns
with diaphragmatic hernia. A certified obstetrician in
Dr. Ken Dewar and his laboratory focus on high-throughput genomic sequencing and sequence analysis to study mammalian evolution and the evolution of gene regulatory sequences. The computational biology group, combined with the sequencing core laboratory of the MUGQIC (McGill University and Genome Quebec Innovation Centre) has continued to develop and advance projects related to genome organization and mammalian evolution, including (1) the identification of a novel retrogene in mice implicated in spermatogenesis; (2) independent evolution of the serpin B cluster in mice and humans; (3) comparative analysis of the HoxA cluster in basal vertebrates; and (4) the development of algorithms and software for navigating large multi-species alignments .
Dr. Eleanor Elstein focuses her research interest on genetic modulation in the cardiovascular system. She is pursuing the study of genetic factors modulating the development of obstructive vasculopathy in cardiac allografts. She has looked at the levels of various aminothiols involved in homocysteine metabolism in heart transplantation. She also has an active clinic in the area of cardiovascular genetics, which evaluates inherited cardiac diseases as well as systemic genetic diseases that have cardiac manifestations.
Dr. Brian Gilfix has received funding from the “Réseau de médecine génétique appliquée” (Fonds de la recherche en santé du Québec) to allow the establishment of techniques and services for the identification of genetic causes of thrombosis among family members. He also currently has ongoing a pilot study examining the frequency of several gene polymorphisms related to obesity in a morbidly obese population.
Dr. William Foulkes and his collaborators have been involved in DNA and tissue profiling in hereditary breast cancer. The most significant achievement in relation to this project was their clear description of the basal epithelial phenotype of BRCA1-related breast cancer. This has several important implications for the origin, and possibly treatment, of BRCA1-related breast cancer. Only a small fraction of all breast cancers have this “basal” character, defined by cytokeratin 5/6 staining. Recent microarray data has shown that basal breast cancers have a particular gene expression profile, and such tumors are usually associated with a poor prognosis. They have gone on to show that the basal epithelial phenotype of BRCA1-related breast cancer does indeed have a “tissue profile” which is consistent with the results obtained from expression microarray analyses. They think this finding will prompt further research into establishing the cell of origin of BRCA1-related breast cancer.
A second achievement was their demonstration that
that BRCA1-related breast cancers do not obey the expected size-nodes
rule. That is, large breast cancers are associated with a greater number of
positive axillary lymph nodes than are small breast cancers. This relationship
is linear, but the slope of the curve is much flatter for BRCA1-related
breast cancers than for either non-BRCA1/2-related breast cancers or BRCA2-related
breast cancers. This suggests that BRCA1-related breast cancers do not
“play by the same rules” that apply to non-BRCA1/2-related
breast cancers. This has implications for early diagnosis of BRCA1-related
breast cancers. This work was published in Cancer in 2003 and was
featured in the
Another achievement was the combined analysis of
survival following a diagnosis of hereditary breast cancer. Here Dr. Foulkes
joined forces with
Other ongoing projects in Dr. Foulkes’ laboratory include studies in hereditary colorectal cancer and, an analysis of the role of known polymophisms and/or mutations in the etiology of prostate cancer.
Dr. Thomas Hudson directs the rapidly expanding
Dr. Kenneth Morgan has his main research interests in population genetics, pedigree analysis, and genetic modelling. He leads a Genetic Analysis Group that participates in two Networks of Centres of Excellence programs: the Canadian Genetic Diseases Network (CGDN) and the Mathematics of Information Technology and Complex Systems. His group is involved in the genetic analysis of Mendelian and complex traits in humans, mice and chickens. He is also an investigator in the McGill University and Genome Quebec Innovation Centre participating in the genotyping core facility, and in mentoring statistical genetic analysis in the regulatory genetics project.
· In studies of the Hutterite population, Dr. Morgan’s group has found that two mutations in two different genes account for all known cases of limb-girdle muscular dystrophy. One of these mutations in the FKRP gene is also found in other populations. A paper on the clinical variability in Bowen-Conradi syndrome, a rare Mendelian congenital malformation syndrome was published, and work proceeded on mapping the disease locus in collaboration with Teresa Zelinski, Cheryl Greenberg, Barbara Triggs-Raine, and Klaus Wrogemann in Winnipeg and Brian Lowry in Calgary.
· By linkage and survival analysis, Dr. Morgan’s group showed that the gene encoding the toll-like receptor 4 plays a role in resistance to salmonella infection in chickens in collaboration with Danielle Malo, McGill University.
· New projects include a collaboration with Alexey Pshezhetsky, Hôpital Ste-Justine, on mapping a locus for mucopolysaccharidosis IIIC (Sanfilippo syndrome) by using a homozygosity mapping approach; and a collaboration with Alain Bonnardeaux, Hôpital Maisonneuve-Rosemont, for which postdoc Loredo-Osti developed methodology for segregation analysis of a quantitative trait in sibships to find evidence for a major gene for urine calcium excretion in families ascertained for kidney stones.
· Dr. Morgan received an Award of Excellence from the Genetics Society of Canada for life-long contributions to genetics, teaching and training in Canada.
Dr. David Rosenblatt and his laboratory continue to be the major international referral source for the diagnosis of patients with inherited disorders of folate and vitamin B12. They are involved in studying the molecular bases of these diseases. In 2003 they reported the first mutations in glutamate formiminotransferase deficiency-the second most common inborn error of folate metabolism. Last year they reported the cloning of the MMAA and MMAB genes responsible for the cblA and cblB forms of vitamin B12-responsive methylmalonic aciduria. In 2004, comprehensive analysis of mutations in the MMAA gene in the cblA form of vitamin B12-responsive methylmalonic aciduria was completed and work continues on the comprehensive analysis of mutations in MMAB in patients with the cblB form of this disease. Ongoing work includes a complete mutation analysis in methylmalonyl CoA mutase deficiency (classical methylmalonic aciduria) in over 150 patients. A common mutation and haplotype has been found in a number of patients of Hispanic origin. With his collaborators Dr. Selzer and Dr. Hogan, Dr. Rosenblatt published an article in the New England Journal of Medicine, warning that a deficiency of MTHFR (methylenetetrahydrofolate reductase) could be a risk factor for those undergoing anesthesia with nitrous oxide.
Dr. Guy Rouleau is an expert in neurogenetics and has varied research interests in this area: defining the role of genetic factors predisposing to the disease amyotrophic lateral sclerosis; searching for genetic factors predisposing to schizophrenia using subjects from different founder populations; identification of a number of loci that predispose to the development of Tourette syndrome; searching for genes predisposing to the development of bipolar disease by focusing on subjects with an excellent response to lithium; characterizing the French Canadian founder effect in a number of different genetic diseases; identification of loci and genes predisposing to the development of autism; further investigation of oculopharygeal muscular dystrophy; mapping restless legs syndrome genes; and, further characterization of the genetic basis for cavernous angioma.
Dr. Patricia Tonin and her laboratory have two principal areas of research interest. 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.
A. The Molecular study of Human Epithelial 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. Members of Dr. Tonin’s laboratory have shown deletions in low grade, early stage tumours and therefore 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 a CIHR funded projects, are to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. Previously, they published a deletion map of chromosome 3p deletions observed in a large series of epithelial ovarian tumours. In addition they are applying a candidate gene approach and have excluded known candidates, such as TGF-ß-RII. They described a chromosome 3 transcriptome based on the comparison of expression profiles of ovarian cancer cell lines with normal surface epithelial cells using high throughput oligonucleotide expression microarrays. In this study they were able to establish the sensitivity of detection and show that subtle changes in gene copy number are detectable by microarray analysis. In an effort to characterize the putative TSG on chromosome 3p implicated in ovarian tumourigensis, they established the relationship between chromosome losses frequently associated with specific regions of the human genome (BRCA2 and 13q, TP53 and 17p, BRCA1 and 17q, and Xp11) with that of 3p regions lost in ovarian cancer. They established chromosome 3p loss occurs independently from TP53 mutagenesis. Most recently they have described the transcriptome of chromosome 17 mapped genes.
B. Breast Cancer Susceptibility Genes: BRCA1 and BRCA2
Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers and large majority of hereditary cancer families are attributed to germ line mutations in BRCA1 and BRCA2, which confer an increased susceptibility to both breast and ovarian cancer. Dr. Tonin’s group is continuing to further define the spectrum of mutations in the BRCA1 and BRCA2 cancer susceptibility genes in the French Canadian population of Quebec.
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