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May 22, 2003, Gazette

Molecular pathology of colorectal cancer
In search of defective genetic mechanisms

Dr. Desmond Robb
Photo by HSIMS
Dr. Desmond Robb

Dr. Desmond Robb, Discipline of Laboratory Medicine, is a member of the Colorectal Cancer Interdisciplinary Health Research Team. Researchers at Memorial University and the University of Toronto are developing and strengthening resources for colorectal cancer research in Ontario and Newfoundland; a major undertaking is to collect information from patients with colorectal cancer in Newfoundland, and from their family members. This information relates to various aspects of patient clinical presentation, family history, lifestyle and tumour molecular pathology.

Dr. Robb is studying DNA abnormalities in mismatch repair genes in colorectal cancer, which he believes may have an important bearing both on patient survival and the need to effectively screen for certain types of colorectal cancer. Under normal circumstances, healthy tissue cells are maintained by efficient genetic mechanisms which ensure that any abnormal DNA formed is repaired or eliminated. If these mechanisms are defective, the cells are liable to accumulate abnormal DNA and develop into malignant cells.

Dr. Robb explained that hereditary colorectal cancer is due to the occurrence, in families, of a germline carrier state of mutations in one of two important genes, known as MLH1 and MSH2, involved in DNA mismatch repair.

PhD student Patti McCarthy (L) and laboratory technologist Cathy Searle
PhD student Patti McCarthy (L) and laboratory technologist Cathy Searle work with Dr. Robb.

“Those defective genes can be passed on from one generation to the next,” he said. “A carrier of a mutated DNA mismatch repair gene is significantly at risk for the development of this hereditary form of colorectal cancer. Abnormalities of DNA mismatch repair may also be found in a subgroup of cases of the more common non-hereditary colorectal cancer, but these apparently arise by different genetic mechanisms which are not hereditary.”

In the laboratory, Dr. Robb assesses the extent of DNA mismatch repair in tumours by measuring the expression of relevant genes using immunohistochemical staining on sections of tumour tissue. Loss of expression of a particular DNA mismatch repair gene means that the tumour cells are unable to repair their abnormal DNA. Additional DNA laboratory techniques are used to confirm the loss of repair gene expression and to ascertain the types of mechanisms underlying the defects in DNA mismatch repair. One of these techniques detects microsatellite instability (MSI), the direct result of failure of DNA mismatch repair.

Dr. Robb said this work, although time-consuming, is not difficult to do. He is excited about the possibility that the study may herald the start of a phase in which we begin to get a real understanding of the biological mechanisms underlying the development of hereditary and non-hereditary colorectal cancer. His specific interest, at present, is to clearly identify the biological differences between tumours with defective DNA mismatch repair and those in which this repair process is normal.

“Such studies may have important consequences for both the assessment of prognosis and the selection of the best possible treatment for the patient.”