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Molecular Markers of Gastrointestinal Cancers
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Cancer is one of the major causes of morbidity and mortality in modern life. It is a special type of genetic disorders that stems from a single cell that undergoes abnormal mutations. These result in abnormal division and proliferation that affect the entire body. Recently, it was found that, for a tumor to develop, there should be series of sequential mutations. Epidemiological, morphological and experimental evidences support this suggestion. Epidemiologically, there is association between tumor and old age group. This indicates the time required for mutations to accumulate. The morphological studies of the colorectal cancer is another evidence. When studying a single tumor containing malignant and benign cells, it appears that the malignant cells have the same mutations as the benign ones, with additional mutations. Experimentally, transferring one oncogene to a cultured fibroblasts results in no changes, while transferring two oncogenes simultaneously, results in abnormal growth. These three sets of evidence give a strong support for the multistep nature of tumorigenesis.(1)
The difference between cancer and other genetic disorders is that in cancer,
accumulation of sequential mutations is needed for cancer to occur. These
sequential mutations occur in special types of genes that are referred to as
oncogenes. These are responsible for regulating cell growth.(1) These genes are
classified into three types: pro-oncogenes, tumor suppressor genes and mutator
genes. The oncogenes are genes that accelerate cell growth.(1,2) Examples are
the Rous chicken sarcoma (src), the Avian chicken myelocytomatosis (c-myc),
bcl-2 and the Kirsten murine rat sarcoma (k-ras).(1,3) On the other hand, tumor
suppressor genes stop cell division and growth.(1,2) Examples of tumor
suppressor genes are the retinoblastoma gene (RB) on chromosome 13q, the Wilm's
tumor gene (WT1) on chromosome 11p, the gene deleted in colon carcinoma (DCC) on
chromosome 18q, the neurofibromatosis type 1 gene (NF1) on chromosome 17q, the
p53 gene on chromosome 17p and the gene involved in familial adenomatus
polyposis coli (APC) on chromosome 5q.(1) The third type of genes, which are the
mutator genes, are recently discovered and their function is to control the rate
of mutations of other genes, including the oncogenes and the tumor suppressor
genes.
For the normal cells to transfer to malignant ones, several gene mutations are needed. The first mutation to a single somatic cell leads to a limited expansion of its progeny. If one of the progeny exposed to another mutation, a small benign tumor will develop. When a cell from that benign tumor undergoes a third mutation, this lead to development of advanced tumor. And, if it acquires more mutations, malignancy results.(1)
This general scenario which shows the association between the genetic
events and the pathophysiological mechanisms of the cancer is supported by the
well-defined morphological stages of the colorectal cancer. The sequence of
mutation are shown in Fig: 1. The start point of transformation to malignancy is
the loss of the APC, the tumor suppressor gene which leads the normal colorectal
epithelium to hyperproliferate. The normal APC gene prevents the binding of ?-catenin
(a cell adhesion molecule) to Tcf-4, (activates gene transcription) that,
subsequently prevents c-myc oncogene expression. This means that mutations of
APC or ?-catenin switch on the expression of c-myc, which promotes uncontrolled
cell growth.(5) The second step of the tumorigenesis is not clear. It could be
either a mutation in the remaining APC allele, or a mutation in another gene
which is not yet identified. This step leads to the formation of early benign
adenoma. The third step is the mutation of one of the benign adenoma cells that
leads to the activation of k-ras oncogene, which subsequently leads to further
expansion and formation of intermediate adenoma. Late adenoma stages and
carcinoma result when sequential mutations occur in DCC and p53 tumor suppressor
genes.(1)
There are different families that have a predisposition to two different types of colorectal cancer that arise in the inner lining. This predisposition is due to the inheritance of mutated APC gene. These are the familial adenomatous polyposis (FAP) and the hereditary nonpolyposis colorectal cancer (HNPCC). In the first type, there is a defect in the tumor initiating gene, APC, that result in developing of thousands of adenomas throughout the colon and rectum. The APC gene lose it ability of initiating the programmed cell death, so the birth will overcome the cell death which initiate the tumorigenesis. In the second type, the defect is in the progression of the tumor. Here, only one or few tumor develops in the colon. This type is caused by inherited defects of mismatch-repair genes.(2)
Cancer is a special type of genetic disorders that require a series of mutations to occur. There are three types of oncogenes: pro-oncogenes, tumor suppressor genes and mutator genes. Mutations of these genes are considered as molecular markers of the tumor. The colorectal cancer is the most well defined cancer that initiated by a mutation in the APC gene. The studies of cancer genetics give a hope of developing a drugs that could interfere with the tumorigenesis.
[1] Vogelstein B, Kinzier KW. The multistep nature of cancer. TIG 1993; 9:138-141 [2] http://www.hhmi.org/science/genetics/vogelstein.htm [3] Mueller RF, Young ID. Emery’s Elements of Medical Genetics. Edinburgh, Churchill Livingstone 1995 [4] Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and
prognosis in colorectal cancer. The New England Journal of Medicine 1994;
331:213-221
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Introduction