High-Risk Familial, Non-Syndromic Colon Cancer Population-based studies have led to estimates that 0.8% to 2.3% of all CRC cases meet the Amsterdam I or II criteria for Lynch syndrome [55]. A subset of these “Amsterdam positive” cases, estimated at 40% to 70%, do not have MMR deficiency and therefore have been termed ‘familial colorectal cancer type X’ [55–57]. Study of these kindreds has revealed that CRC risk is lower than in Lynch syndrome and that CRC diagnosis averages 10 years later. Additionally, tumors do not exhibit MSI, and there is no increased incidence of extra-colonic malignancies. Surveillance recommendations are based on family history and are described below. The yet-to-be identified susceptibility gene or genes for this “type X” are likely to be uncommon but sufficiently penetrant to give rise to the observed autosomal dominant segregation patterns. Identification of the relevant genes will allow development of genetic testing and more precise surveillance strategies.Common Familial Risk Colon Cancer Individuals who have a first-degree relative with CRC diagnosed over age 50 years have a 2–3-fold increased risk for this malignancy. Population-based studies have demonstrated that approximately 20% of all CRC cases occur in a higher risk setting; CRC under age 50 or a first-degree relative pair with CRC [55]. Furthermore, having one first-degree relative with CRC under age 45 years, or having two first-degree relatives affected with CRC confers a 3–6-fold CRC risk compared to the general population [58]. Sibling pair and parent/child pair studies have identified chromosomal regions that could contain genes that confer this level of risk; these include 7q31, 9q22.33, 3q21-24, and 11q23, with some minor loci that have been identified in more than one study [59–62]. CRAC1 (also known as hereditary mixed polyposis syndrome, HMPS) has a similar risk level and has been associated with colon cancer by linkage analysis in Ashkenazi Jewish families [63] and in sibling pair studies [64]. These reports support the paradigm that common familial CRCs arise from a number of different, lower-penetrance susceptibility genes than those associated with the well-defined but rare inherited syndromes. These intermediate penetrant genes likely constitute only a small portion of the colon cancer population. Otherwise they would be detected by genome-wide association studies, where commonly occurring but very low penetrant susceptibility loci are detected. [65]; Indeed the genetic loci identified through family linkage and affected relative pair studies do not usually overlap with the susceptibility loci identified in genome-wide studies---see below.
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