Molecular Cytogenetics of Solid Tumours and Chromosomal Instability in Cancer

This laboratory's program is strongly oriented towards translational research (see web site: http://www.utoronto.ca/cancyto/ for details) using molecular, genomic and cytogenetic methods to provide new information and hypotheses concerning the onset, cause and progression of cancer. The program continues to involve close interactions between basic scientists and clinicians from the disciplines of Pathology, Oncology and Genetics. This laboratory has published well over 100 original peer-reviewed papers in the area of the molecular cytogenetics of solid tumors and leukemias. Current research interests centre on genomic alterations associated with preneoplasia and in chromosomal mechanisms that lead to the onset of translocations, amplification and deletions in tumors.

Recent findings of have focused on the nature and location of gene amplification and deletion in tumors, and are now systematically analyzing flanking sequences that may facilitate tumor-specific genomic rearrangements in the context of homologous dependent repair pathways. These deletions are probably facilitated by repetitive DNA elements and duplications that flank translocation breakpoints. Microarray, genomic, and more advanced molecular cytogenetic imaging methods have recently provided additional clues to this process in tumors. With Dr. Maria Zielenska's laboratory (HSC) the group has had a long-standing interest in the molecular genetics of osteosarcoma. In addition studies focus on chronic myeloid leukemia (with Dr Dwayne Barber,OCR), prostate and ovarian cancer (with Dr Pascale Macgregor and others). A long-standing collaboration with Dr. Rosanna Weksberg (HSC) has
involved the study of 'epigenotypes' and imprinting alterations associated with tumour predisposition.

A key finding last year came from Bisera Vukovic in the prostate cancer group in this laboratory. She demonstrated that the stabilizing telomere sequences at the tips of each chromosome get significantly shorter in certain types of preneoplastic prostate cells. This observation may pave the way for future laboratory tests to identify men at a greater risk of prostate cancer.

For further information, please visit my laboratory homepage at http://www.utoronto.ca/cancyto/

Selected References:

Vukovic B, Park P, Al-Maghrabi J, Beheshti B, Sweet J, Evans A, Trachtenberg J, and Squire JA. Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma. Oncogene 22(13): 1978-1987, 2003

Kolomietz E, Yee K, Marrano P, Braude I, Kolomietz A, Thai B, Chun K, Minkin S, Kamel-Reid S, Minden M, and Squire JA. Quantitative PCR identifies a minimal deleted region of 120 kb extending from the Philadelphia chromosome ABL translocation breakpoint in chronic myeloid leukemia with poor outcome. Leukemia 17(7): 1313-1323, 2003.

Squire JA, Pei J, Marrano P, Beheshti B, Bayani J, Lim G, Moldovan L, and Zielenska M. High-resolution mapping of amplifications and deletions in pediatric osteosarcoma use of CGH analysis of cDNA microarrays identifies an association with segmental duplications. Genes Chromosomes Cancer 38(3): 215-25, 2003

Evans AJ, Gallie BL, Jewett MA, Pond GR, Vandezande K, Underwood J, Fradet Y, Lim G, Marrano P, Zielenska M, Squire JA. Defining a 0.5 Mb region of genomic gain on chromosome 6p22 in bladder cancer by quanititative-multiplex polymerase chain reaction. Am J. Pathology, 164(1): 285-293, 2004

Macgregor P. and Squire JA. Application of Microarrays for the Analysis of Gene Expression in Cancer. Clinical Chemistry. 48(8): 1170-1177, 2002. (Review)

Beatty B, Mai S, and Squire JA. Editors of 'FISH: A Practical Approach', The Practical Approach Series. Oxford University IRL Press, 2002. (book)