12th Ljudevit Jurak
International Symposium on
June 1-2, 2001
|MOLECULAR GENETICS OF COLON CANCER
Division of Molecular Medicine, Ruðer
Boškoviæ Institute, Zagreb, Croatia
|Molecular genetics of cancer has received large attention during the
past decade. It is now quite evident that cancer is a genetic disease,
caused by inherited or acquired mutations in different oncogenes
and tumour suppressor genes, and that carcinogenesis is a multi-step process.
Colorectal cancer develops through a sequence of genetic alterations responsible
for the progression from normal colonic mucosa to carcinoma, through the
so-called “adenoma-to-carcinoma” sequence. These alterations include mutations
in the K-ras oncogene and loss of heterozygosity of tumor suppressor genes
such as APC, DCC and p53. Epidemiological studies have suggested that at
least 15% of colorectal cancers occur in dominantly inherited patterns.
The two best defined familial forms are FAP and HNPCC. In the past five
years, the genetic bases for both of these syndromes have been discovered.
Familial adenomatous polyposis (FAP) is an autosomal, dominantly inherited
disease that predisposes to colorectal cancer and is characterized by the
presence of hundreds to thousands of adenomas covering the colon and rectum.
If left untreated, patients have a very high risk of developing cancer
during the second and third decades of life. The mutation of the tumor
suppressor gene APC (adenomatous polyposis coli), discovered in 1991, was
found to be the cause of FAP. At least four genes that participate in mismatch
repair are implicated in the pathogenesis of the second form of hereditary
colon cancer HNPCC (hereditary non-polyposis colorectal cancer): hMSH2,
hMLH1, hPMS1 and hPMS2. Defective genes responsible for DNA mismatch repair
(MMR) result in an increase of replicative errors at microsatellite sequences
that result in insertions and deletions (microsatellite instability MS).