Common Familial Colon Cancer
All Mendelian colorectal cancer predisposition syndromes described so far represent just » 5% of the total number of colorectal cancers. Between15-20% of patients with colorectal cancer present familial aggregation. A meta-analysis of epidemiologic studies showed having a first-degree relative with colon cancer doubled the risk of developing that malignancy and, if the affected relative was diagnosed before the age of 45 years, the risk was increased nearly 4 fold . A twin study indicated that about 35% of all colorectal cancers could be ascribed to an inherited susceptibility.
It has been hypothesized that this significant percentage of familial clusters are likely due to interactions among multiple genes and genetic-environmental interactions. Some studies are pointing at genes that would be implicated with a low-penetrance inheritance. Thus, I1370K polymorphism in the APC gene is present in the germ-line DNA from almost 6% of Ashkenazi Jews, resulting in a two fold increased risk for colorectal cancer development.
Other studies have shown that alterations in Harvey ras-1 variable number tandem repeat polymorphism (HRAS1-VNTR), located 1Kb downstream of the oncogen H-ras1, also confer an increased risk of colorectal cancer. Finally, TGFBR1 * 6A variant has been associated with a nearly 1.6%-fold increase risk of colorectal cancer in a number of cases and controls from the USA. But this has not been confirmed in a recent European study, underlying the difficulty of studying low-frequency alleles in stratified populations. Finally, very recent reports from the same group have pointed at CRAC1, SMAD7 and a region in 8q24.21 as new susceptibility variants for colorectal cancer development.
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