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MD, University of Toronto
Hospital for Sick Children
Peter Gilgan Centre for Research and Learning (PGCRL-SickKids Research Tower)
686 Bay Street, Room 18-9705
Phone: (416) 813-5348
Email Dr. David Malkin
Genetic Determinants of ChildhoodCancer Predisposition
Almost every type of cancer has been reported to occur in a familial form. Li-Fraumeni syndrome (LFS) is a paradigm cancer predisposition syndrome in which affected family members develop a wide spectrum of cancers including sarcomas, breast cancer, brain tumors and adrenocortical carciomas at very young ages. Many affected individuals develop multiple cancers during their lifetime and these cancers frequently occur at ever younger ages with each subsequent generation. We have previously found that constitutional (inherited or de novo) mutations of the p53 tumour suppressor gene are associated with cancer predisposition in many of these families, as well as in patients with multiple primary cancers, and children with osteosarcoma, rhabdomyosarcoma, choroid plexus carcinoma or adrenocortical carcinoma in the absence of a family history of cancer.
Our research focuses on the genetic basis of LFS, and particularly on the epigenetic and molecular cellular events that modify the underlying constitutional mutant p53 genotype in LFS families. We have recently demonstrated that accelerated telomere attrition measured in peripheral blood lymphocytes is associated with accelerated tumor onset in successive generations, and that this early onset is further influenced by the existence of a variable single nucleotide polymorphism (SNP) in the hMDM2 gene. We are now examining the role of telomere dysfunction and
telomerase function in the context of constitutional p53 genotypes, as well as in specific subsets of LFS tumors. We are also utilizing high-throughput genome-wide array analyses to explore the interaction of other elements of the human genome in modulating the phenotypic variations found in LFS in the context of distinct underlying p53 alterations. Our goal is to develop an understanding of the underlying genetic basis of cancer predisposition in these cancer-prone individuals, and to eventually develop a molecular metric that may inform clinical surveillance opportunities for early tumor detection.
To complement our genetic approach to LFS, we are exploring the cell signaling mechanisms involved in the initiation and progression of rhabdomyosarcoma (RMS) – a tumor derived from immature skeletal muscle elements that represents the most common childhood cancer in LFS, and the most common sporadic soft tissue sarcoma of childhood. We have previously demonstrated that RMS cells express vascular endothelial growth factor receptor (VEGFR) and are responsive to VEGF ligand. Inhibition of this ligand-receptor interaction leads to growth inhibition of RMS cells. We are interested in determining the functional interaction of this kinase pathway with other p53- dependent and independent signaling mechanisms in RMS. Characterization of these functional pathways may lead to the identification of novel molecular therapeutic targets for these aggressive malignancies.
List of Key Publications:
Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer inititation is associated with shorter telomere length in Li- Fraumeni syndrome. Cancer Res 67(4): 1415-18, 2007.
Strahm D, Durbin AD, Sexsmith E, Malkin D. The CXCR4- SDF1 axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma. Clin Exp Metastasis Sep 1, 2007. [epub ahead of print]
Tabori U, Vokovic B, Zielenska M, Hawkins C, Braude I, Rutka J, Bouffet E, Squire J, Malkin D. The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas. Neoplasia 8(2): 136-142, 2006.
West NA, Neale GA, Pounds S, Figueredo BC, Rodriguez- Galindo C, Pianovski MA, Oliveira Fiho AG, Malkin D, Lalli E, Ribeiro R, Zambetti GP. Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67(2): 600-8, 2007.
- James Tran