by Amira Sanki, Wei Li, Marjorie Cloman, Rooshdiya Z. Karim, John F. Thompson, and Richard A. Scolyer. Pathology (2007). 39(6), pp. 551-557.
Summary
Tumor suppressor genes encode proteins that act to prevent or suppress the formation of cancerous tumors. These proteins affect the cell cycle, either by preventing unchecked proliferation (negative regulation) and/or by inducing apoptosis, or programmed cell death (positive regulation) [1]. When mutations in these genes occur, tumor formation can result and the cells may become malignant*. For example, an estimated 50% of all cancers are associated with a mutation in the p53 tumor suppressor gene [2]. Sanki et al. studied the relationship between a reduction in the p16 and p27 tumor suppressor gene products and melanoma, a cancer of the melanocytes and the most lethal form of skin cancer (see below; Skin Pathology).
Most of our body's normal cells progress through four stages: G1, S, G2, and M, during which the cells grow, synthesize DNA, and eventually divide. The cycle is controlled by cyclin dependent kinases (CDKs) and cyclin dependent kinase inhibitors (CDKIs). CDKs form complexes with cyclins by phosphorylating them, which together phosphorylate other proteins. The result is the release of transcription factors, which allow for the progression of the cell cycle. CDKIs block this progress by preventing the initial phosphorylation of cyclin by CDK. The CDKIs, which include p16 and p27, act in response to DNA damage which would prevent proper functioning of the cell. By stopping the cell cycle before division, the DNA can be repaired, ensuring survival of the cell. A reduction in the expression of these proteins therefore leads to the uncontrolled progression of the cell cycle, and is associated with a number of conditions including cancer of the pancreas, esophagus (p16), bowel, breast, and prostate (p27).
Sanki et al. discussed research in the areas of tumor suppressor genes and melanoma conducted prior to their findings. A genetic link has been established between a family history of melanoma and risk to the individual. For a patient with three or more first degree relatives diagnosed with melanoma, the risk of developing the condition increases by 35-70%. 30-40% of families with three or more members with melanoma have mutations in the CDKN2a gene, which encodes p16. Earlier research has also suggested that a high number of atypical naevi* increases the risk of developing melanoma.
A total of 92 melanocytic lesions, both benign* and malignant, were tested using immunohistochemistry* for the presence of p16 and p27. Antibodies to the proteins were made and allowed to bind to the p16 and p27 antigens. The amounts of these proteins present in the samples were determined by observing staining intensity and applying a staining score. The number of stained cells in each sample was also recorded.
Critique
I chose this paper based on its discussion of tumor suppressor genes and their role in cancer, a topic I find interesting and important to genetics and cancer research. With more than 4,600 new cases of melanoma reported in Canada in 2007 alone [3], research into the cause of this disease may provide insight into treatment and possibly, in the future, a practical cure.
The purpose of the researchers in writing this paper was clear and thoughtfully planned out. Their method of using immunohistochemistry to observe the presence of p16 and p27 in the samples was clever and effective. However, their method of assigning a staining value to the cells was objective and a matter of personal perception. They circumvented this by having the values assigned by a single pathologist. The paper contained a number of figures that demonstrated their findings (see Figure 1 above), which clearly differentiated between strong positive (protein present) and strong negative (protein absent) results. To someone unfamiliar with research in the area of tumor suppressor genes and cancer, the foreign terminology used could be confusing, if not completely incomprehensible. However, they do attempt to explain some background information with a nice description of the cell cycle and its components in the paper's introduction.
Overall, I found this paper to be a well-written and concise illustration of the association between p16 and p27 and melanoma. The results are promising, and may some day lead to a successful treatment or preventative cure. I would very much like to see further research into the role of tumor suppressor genes in skin cancer and other malignancies.
Definitions
Benign: not cancerous; not capable of invading nearby tissue or spreading to other parts of the body.
Immunohistochemistry: a method that uses antibodies to identify, locate, and stain specific protein molecules in tissue sections
Malignant: cancerous; capable of spreading to other parts of the body
Metastatic: the spread of cancer from the primary site or origin to distant sites in the body
Naevi: pigmented lesions of the skin; moles
References
[1] Griffiths, A. J F., Gelbart, W. M., Lewontin, R. C., and Miller, J. H. (2002). Modern Genetic Analysis. 2nd ed. W. H. Freeman and Company.
[2] Benjamin, C. L., Melnikova, V. O., and Ananthaswamy, H. N. p53 protein and pathogenesis of melanoma and nonmelanoma skin cancer. Adv. Exp. Med. Biol. 2008; 624:265-82.
[3] Canadian Cancer Society, National Cancer Institute of Canada, Statistics Canada, and Provincial/Territorial Cancer Registries. (2007). Canadian Cancer Statistics 2007.
No comments:
Post a Comment