BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

SECTION 16. ONCOGENESIS

V. Multistep Carcinogenesis Theory in a Colorectal Cancer Model

Colorectal Cancer is one of the most common types of malignant tumors. The majority of cases of this Etiology begin with The formation of benign tumors called adenomas. Based on a comparison of characteristic chromosomal karyotypes, oncogenes, tumor suppressor genes, and DNA Methylation levels in samples of normal colorectal tissue, adenomas of various sizes, carcinomas, and colorectal cancer metastases, a model has been proposed that outlines The sequence of events during colorectal carcinoma development.

As shown in Fig. 16-14, The Development of cancer is preceded by 5 – 7 Mutations in oncogenes and tumor suppressor genes, DNA hypomethylation, and impairments in DNA Repair systems. Early events in this process include mutations in a tumor suppressor Gene localized on chromosome 5. These are found in patients with familial adenomatous polyposis (FAP), which led to the corresponding naming of the gene (the FAP gene).

Class="center">Fig. 16-14. Genetic model of colorectal cancer development. Early adenomas are less than 1 cm in diameter; intermediate adenomas are larger than early adenomas. Late adenomas exhibit foci of cancer Cells.

The Cytology/cytology/16.html">Early stages of the process involve a decrease in DNA methylation levels and the activation of the ras oncogene on chromosome 12, both of which promote adenoma growth. Defects in DNA repair systems, along with the loss or inactivation of tumor suppressor genes, lead to genetic instability and tumor malignancy. The exact sequence of these changes is less critical than the cumulative total of genomic alterations. Dedifferentiation and the ongoing accumulation of mutations grant tumor cells the capacity for Invasion and Metastasis.

Impairments in the DNA repair system responsible for correcting Replication errors have been observed in hereditary nonpolyposis colorectal cancer and tumors of certain other Tissues. In these cases, microsatellite instability occurs. Microsatellite sequences are short, non-coding DNA sequences that are repeated numerous times throughout The Genome. Unlike normal tissue, tumors exhibit variations in the length of microsatellite sequences, indicating that tumor cells either lose or gain extra NUCLEOTIDES. This phenomenon can occur when two DNA strands slip relative to one another during replication. Depending on the direction of the slippage, the newly synthesized DNA strand will be either shorter or longer than the template strand. As a result, the newly synthesized double-stranded DNA will contain small loops of unpaired DNA, which are normally corrected by the repair system in healthy tissues. In tumors, this system is defective; for instance, mutations in genes encoding repair complex Proteins have been detected in virtually all cases of colorectal cancer.