What is the role of genetics in the pathogenesis of colorectal tumors?

Updated: Jun 06, 2020
  • Author: Jaime Shalkow, MD, FACS; Chief Editor: Cameron K Tebbi, MD  more...
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The unwinding and copying enzymes that replicate DNA form a highly efficient and accurate replicative complex. However, this process is not perfect. Mistakes in base pairing occasionally occur. Some stretches of DNA are more likely to accumulate errors than others, particularly stretches of DNA that consist of tandem-repeat units. These areas are termed microsatellite regions. Certain patients have marked instability in the microsatellite repeats throughout their genomes; this instability leads to a failure to recognize and repair these nucleotide mismatches. Mismatch repair defects are an early step in the process leading to malignant transformation.

The progression from normal to dysplastic colonic epithelium begins with hyperplasia, followed by the development of adenomas and, finally, invasive carcinomas. Most mutations that occur in colon cancer develop after birth in single cells as a result of exposures to environmental influences or perhaps as a result of mistakes that cells make when they copy their DNA during cell division. Approximately 80% of annual cases of colorectal carcinoma (CRC) are not associated with hereditary factors.

The progression of adenoma to carcinoma depends on reproducible genetic alterations such as APC gene inactivation, K-ras oncogene activation, and p53 mutation.

Mutations in the APC gene, a tumor suppressor gene that controls tumor initiation, are present in 80-90% of patients with familial adenomatous polyposis (FAP). [24, 35] When the APC gene is mutated, the function of both APC alleles is lost. One allele is defective at birth in all cells, having been inherited from one parent; the other APC gene allele is mutated in individual colon cells during early childhood, supporting the 2-hit hypothesis by Knudson. [36]

Malignant progression from the development of hyperplasia takes 20-30 years. This is because the tumors have to accumulate other mutations in oncogenes and other tumor suppressor genes that convert the benign adenoma into a malignant tumor.

In contrast, defects in DNA repair, particularly a DNA repair system termed DNA mismatch repair, cause hereditary nonpolyposis colon cancer (HNPCC). The enzymes that copy DNA are not perfect and often make mistakes. This mismatch must be repaired in order to avoid mutations. The DNA mismatch repair system recognizes the DNA mismatch and repairs it. [37]

Patients with HNPCC do not have defects in the APC gene inherited from their parents. Benign tumors (ie, adenomas) develop at the same rate in these patients as in the general population; however, once a patient with HNPCC has an adenoma, it rapidly progresses because of the inherited DNA repair defect. Mutations involving tumor suppressor genes and oncogenes rapidly accumulate, and, as a result, only 3-5 years are needed for a benign tumor to progress to cancer. FAP may be considered a disease of tumor initiation, whereas HNPCC may be considered a disease of tumor progression. [38]

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