Colorectal
cancer is one of the most common malignant diseases. Many colorectal cancers originate from benign adenomas as in
as in case of Familial Adenomatous Polyposis (FAP). FAP has an incidence of approximately 1:10,000 and is an
autosomal dominant disorder with high penetrance and highly variable
expressivity. The genetic
defect is characterized by the development of numerous (one hundred to
several thousand) colorectal polyps.
The age of onset of these polyps is variable but usually develop
in the second or third decade of life.
The likelihood that they will develop colorectal cancer is almost
100% unless they are treated by prophylactic colectomy.
Polyps may occur in the upper gastrointestinal tract through risk
of malignant transformation is lower than for colonic adenomas.
Extraintestinal manifestations of the disease include epidermoid
cysts, ostemas, desmoid tumors and congenital hypertrophy of the retinal
pigment epithelium (CHRPE).
The gene responsible for the disease is APC (adenomatous
polyposis coli) located at 5q21-22.
About 200 different germline mutations in the APC gene have been
described. Most of the
mutations lead to the termination of the protein chain. The APC gene
consists of 15 exons with an open reading frame larger than 8.5kb, so it
is difficult to screen or sequence this rapidly.
Methodology
Protein Truncation Test (PTT) detects mutations at the protein
level rather than the DNA level. The
DNA is first transcribe into messenger RNA and then translated into
peptide chain. Mutational
changes (bases changes resulting into nonsense or stop codons)
prematurely terminate translation and produce a truncated protein which
is smaller than the normal size protein.
Since majority of the mutations (greater than 85%) in the APC
gene are associated with inherited form of colon cancer and result in
protein truncation, the PTT test is being used as a direct test for
mutation detection.
References
Ward, J.T. et al. Genomics 17:15 (1993)
Lynch, H.T. et al Cancer Gen. Cyto. 93:84 (1997)
Powell, S.M.et al N.Engl.J.Med. 329:1982 (1993)
