Annual Report 2000/2001 Annual Report |
Annual Report 2000/2001
The Hess B. and Diane Finestone Laboratory in Memory
of Jacob and Jenny Finestone was established to promote the field of medical genetics at
McGill University. Dr. David S. Rosenblatt
has been the director of the Laboratory since its inception. The laboratory was established with the help of a
million-dollar endowment to McGill and is housed on the fifth floor of the Hersey Pavilion
of the Royal Victoria Hospital. Funding from
the Finestone Laboratory is used to advance the academic goals of the Division of Medical
Genetics in the Department of Medicine of the McGill University Health Centre (MUHC). This report serves as the Annual Report of the
Division of Medical Genetics of the Department of Medicine.
It is available on the Internet (http://www.mcgill.ca/finestone/). As of March 2001, Dr. Rosenblatt has been
appointed, Chair of the Department of Human Genetics at McGill.
Celia
Greenwood, PhD was recruited this year to add to the existing strength provided by Kenneth
Morgan, PhD and Mary Fujiwara in the area of genetic epidemiology. David Watkins, PhD and Dr. David Rosenblatt
published their description of a novel complementation class associated with vitamin B12-responsive
methylmalonic aciduria (cblH). Dr. Rosenblatt
and his colleagues expanded the spectrum of mutations causing severe MTHFR deficiency and
found that P1173L is a recurrent mutation in patients with methionine synthase deficiency
(cblG). Dr. Thomas Hudson and collaborators
identified important loci involved in both asthma and diabetes. The Montreal Genome Centre, which he directs,
expanded its capacities and was used by over 50 different laboratories. Patricia Tonin, PhD published a deletion map of
chromosome 17 shown to harbour a tumour suppressor for ovarian cancer. She also collaborated on a study that looked at
the effect of tamoxifen on the risk of contra lateral breast cancer in carriers of BRCA1
and BRCA2 mutations. Kenneth Morgan, PhD and
his collaborators mapped a gene for the autosomal recessive form of childhood cirrhosis in
aboriginal Quebec families. His analysis of
families with a distinctive spastic ataxia contributed to the fine mapping and
identification of the sacsin (SACS) gene. Dr.
William Foulkes published two papers this year on the penetrance and clinical aspects of
hereditary breast cancer.
The
entire structure of clinical services for medical genetics within the McGill University
Health Centre (MUHC) is in the process of being restructured. In the future, there will be a Medical Genetics
Program within the MUHC. It will have
responsibility for the entire range of medical genetic services across all ages within the
MUHC. The details of how the program
will work and its interactions with the Department of Human Genetics at McGill are
currently being defined. This will also allow medical geneticists to participate actively
in the planning for medical genetic services for the new hospital site. With the recognition of the specialty of Medical
Geneticists within Quebec, medical geneticists have been offered the possibility of being
paid by "Remuneration Mixte". Most
accepted this form of payment and this has resulted in a substantial increase in the
potential for clinical earnings. This should
result in a better environment for the recruitment
of medical geneticists to McGill hospitals.
Dr.
Mary-Ann Thomas completed her RI year and is currently an RII resident in Medical Genetics
in our program. She is the first trainee that
has been allowed to start at the RI level at McGill.
Dr. Chantal Morel is currently completing her RI year and we expect two new
residents for the academic year 2001-2002. It
is with great enthusiasm that we look forward to shortly having a full complement of
residents at the RI through the RV levels.
Brian
Gilfix
Dr. John and Clara M. Fraser Award
2000
Admission to the National Academy of Clinical Biochemistry 2001
(Fellow of the National
Academy of Clinical Biochemistry)
Research Interests and
Accomplishments of Individual Members:
Dr.
Valérie Désilets has played a major role in the re-organization of prenatal
diagnosis services within the McGill system. Her
research interests continue to be in the area of first trimester ultrasound screening for
fetal malformations and the use of nuchal translucency as
a method to look for aneuploidy and fetal cardiac malformations in the
general population.
Dr.
Eleanor Elstein focused her research 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 in homocysteine metabolism in heart
transplantation.
Mary
Fujiwara participates in all of the grants and academic activities of Kenneth Morgan,
PhD. Her areas of interest include genetic
epidemiology, analysis of genealogies, linkage analysis and database management.
Dr.
William Foulkes has continued to focus on the historical cohort of women with breast
cancer ascertained at the SMBD-Jewish General Hospital, and also started work on the
significance of particular mutations in HNPCC. His publication highlights for 2000 include
two papers on survival in hereditary breast cancer, a collaboration with the International
Consortium for Prostate Cancer Genetics, further work on familial Wilms tumour, and
studies in head and neck cancer.
His
main research area in 2000 has been the further description of the clinicopathological
features of hereditary breast cancer. In addition, he has started a microarray project in
squamous cell carcinoma of the head and neck, in collaboration with Dr. Moulay
Alaoui-Jamali at the Lady Davis Institute. A new development has been the identification
of mutations in individuals with hereditary
non-polyposis colorectal cancer (HNPCC) in collaboration with Dr. Georges Chong and
colleagues at the Jewish General Hospital. He continued to work with colleagues in Canada
and elsewhere on large multicentre studies of penetrance and clinical aspects of cancer
genetics.
Dr.
Brian Gilfix became a Diplomate of the American Board of Clinical Chemistry (Molecular
Diagnostics). He is one of the first six
individuals to hold certification in this area (certificate #2), and is the only holder of
this certification in Canada.
Dr.
Cecilia Greenwood started her position September 1, 2000; this summary covers
developments in the fall of 2000. She has
been working on developing flexible new methods to incorporate many phenotypic
measurements into linkage analysis. Using
classification and regression trees, she hopes to develop an approach that will adaptively
identify phenotypic subgroups that show strong evidence for linkage. In December 2000, she hired a research assistant
to help in the programming of this endeavour. In
the fall of 2000, she submitted an operating grant application to CIHR, and salary award
applications to CIHR and FRSQ. (In April
2001, she received an FRSQ chercheur-boursier award).
In November 2000, she was a co-investigator on a (successful) application to
Génome Québec, headed by Dr. T. Hudson, that proposes to identify regulatory
polymorphisms.
Dr.
Thomas Hudson and his laboratory continued their complex trait mapping projects:
asthma, coronary heart disease, diabetes and inflammatory bowel disease. The asthma
project primarily involved the analysis of a chromosome 12 atopy locus. They performed high-density genotyping and gene
re-sequencing, in a sample of 175 families from Northeastern Quebec. They have also used this cohort to replicate a
chromosome 7 asthma locus that was identified in Finland: both groups reported this work
in a recent Nature Genetics issue. Polymorphisms in several candidate genes related to
diabetes and obesity were reported: PPARalpha, PPARgamma, glycerol kinase, and
mitochondrial glycerol-3-phosphate dehydrogenase. The Montreal Genome Centre (Directed by
Dr. Hudson) expanded its genotyping, sequencing and DNA chip capabilities. Over 50
laboratories used the expertises of the Centre in 2000.
Kenneth
Morgan, PhD leads the 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 Network. Highlights of his research activity during the
past year included: the analyses of families with a distinctive spastic ataxia, that is
common in northeastern Quebec, that contributed to the fine mapping and identification of
the sacsin gene (SACS) and two disease-causing mutations; in collaboration with colleagues
at McGill, a study of the risk of tuberculosis in an Aboriginal Canadian kindred,
providing evidence that NRAMP1 or a closely linked gene plays a major role in
susceptibility; in collaboration with colleagues at l'Hôpital Ste-Justine, the mapping of a gene for an autosomal recessive form
of childhood cirrhosis in Aboriginal Quebec families; in collaboration with Dr. Daniel
Bichet, the report of 33 novel mutations in the arginine vasopressin receptor (AVPR2) gene
that cause nephrogenic diabetes insipidus. The
majority of Dr. Morgan's work was done in collaboration with Mary Fujiwara who is also a
member of the Division of Medical Genetics.
Dr.
David Rosenblatt and David Watkins, PhD published their description of a novel
complementation class associated with vitamin B12-responsive methylmalonic
aciduria (cblH). Dr. Rosenblatt and his
colleagues characterized the mutations in most known patients with methionine synthase
deficiency (cblG) and found that P1173L is a recurrent mutation that is present in many
patients. With Rima Rozen, PhD six novel mutations in methylenetetrahydrofolate reductase
(MTHFR) were characterized. With
collaborators in France, a novel polymorphism in the reduced folate carrier was identified and its association with folate and
homocysteine status were studied.
Dr.
Guy Rouleau addresses two major themes in his ongoing work. The first theme involves
studies of a number of hereditary neurodegenerative disorders. He performs linkage analysis followed by
chromosomally based cloning of the defective gene and mutation analysis. He 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, the gene for which he has recently cloned. He is attempting to define the molecular events
underlying carcinogenesis in the CNS. His
approach involves linkage analysis, reverse genetics, somatic cell genetics, physical
mapping of human chromosomes, cDNA cloning and characterization, mutation analysis and
cell biology.
Dr.
Rouleau's laboratory has mapped some of the most prevalent genetic diseases in Quebec,
among them, oculopharyngeal muscular dystrophy, hidrotic ectodermal dysplasia and
peripheral neuropathy with or without agenesis of the corpus callosum. These linkage findings have lead to the
development of prenatal and presymptomatic diagnostic tests for these diseases.
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.
1)
Molecular study of Human Epithelial Ovarian Cancer: Our 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 and her collaborators 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 goal of a CIHR funded project is
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 (Manderson
et al., 2000). This year they published a deletion map of chromosome 17q region shown to
harbour a tumour suppressor for ovarian cancer (Dion et al., 2000). In an effort to
characterize a tumour model for epithelial ovarian cancer they have described the
characterization of four spontaneously transformed novel epithelial ovarian cancer cell
lines (Provencher et al., 2000) and the unusual karyotype of trisomy 10 in a selected
number of ovarian cancer cases(Wang et al., 2000). 2)
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 germline mutations in BRCA1 and BRCA2 which confer an increased
susceptibility to both breast and ovarian cancer. Previously, Dr Tonin and her
collaborators established the spectrum of BRCA1 and BRCA2 mutations found in high-risk
families of French Canadian descent. Recently, they have extended this study to
established the frequency of common mutations in unselected breast cancer cases diagnosed
below age 40 years (Tonin et al., 2001). These findings will improve genetic counselling
by facilitating mutation detection. In collaboration with the Breast Cancer Linkage
Consortium (BCLC) they have established the variation in cancer risks by mutation position
in BRCA2 mutation carriers. (Thompson
et al., 2001). In
collaboration with Dr. Steven Narod, they investigated tamoxifen and risk of contralateral
breast cancer in BRCA1 and BRCA2 mutation carriers (Narod et al., 2001).
David
Watkins, PhD along with Dr. David Rosenblatt, published the description of the novel
cblH form of vitamin B12-responsive methylmalonic aciduria. He has begun projects using microcell mediated
chromosome transfer to find genes involved in both inborn errors of vitamin B12
metabolism and in some forms of cancer.
(c)2001 Finestone Labloratory