Between 2% to 5% of all colon cancers arise in the setting of well defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.

Accurate estimation of recent shared ancestry is important for genetics, evolution, medicine, conservation biology, and forensics. Established methods estimate kinship accurately for first-degree through third-degree relatives. We demonstrate that chromosomal segments shared by two individuals due to identity by descent (IBD) provide much additional information about shared ancestry. We developed a maximum-likelihood method for the estimation of recent shared ancestry (ERSA) from the number and lengths of IBD segments derived from high-density SNP or whole-genome sequence data. We used ERSA to estimate relationships from SNP genotypes in 169 individuals from three large, well-defined human pedigrees. ERSA is accurate to within one degree of relationship for 97% of first-degree through fifth-degree relatives and 80% of sixthdegree and seventh-degree relatives. We demonstrate that ERSA's statistical power approaches the maximum theoretical limit imposed by the fact that distant relatives frequently share no DNA through a common ancestor. ERSA greatly expands the range of relationships that can be estimated from genetic data and is implemented in a freely available software package.[Supplemental material is available for this article. The software program ERSA is freely available for academic use at http://jorde-lab.genetics.utah.edu/ersa.]Knowledge about the recent shared ancestry between individuals is fundamental to a wide variety of genetic studies. Detecting cryptic relatedness is a valuable technique for mapping diseasesusceptibility loci and for identifying other at-risk individuals (Neklason et al. 2008;Thomas et al. 2008). For case-control association studies and population-based genetic analyses, related individuals must be identified and removed from samples that are intended to be random representatives of their populations (Voight and Pritchard 2005;Pemberton et al. 2010;Simonson et al. 2010;Xing et al. 2010). Using genetic data to correct pedigree errors increases the power of disease mapping in families (Cherny et al. 2001). Genetic identification of relatives has also proven invaluable in forensic identification of missing persons, victims of mass disasters, and suspects in criminal investigations (Biesecker et al. 2005;Bieber et al. 2006;Zupanic Pajnic et al. 2010). Studies of conservation biology, quantitative genetics, and evolutionary biology are greatly illuminated when the recent shared ancestry between individuals can be reconstructed, especially in agricultural and wild populations (DeWoody 2005;Slate et al. 2010).Most established methods for detecting and estimating genetic relationships are based on genome-wide averages of the estimated number of alleles shared identically by descent (IBD) between two individuals (Weir et al. 2006). These methods are accurate and efficient for relationships as distant as third-degree relatives (e.g., first cousins) but cannot identify more distant relationships. Here we present ERSA, a novel method for estimation of recent shared ancestry. Our method build...

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Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.