Molecular pathology
of colorectal cancer
In search of defective genetic mechanisms
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| 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.
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| 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.”
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