During the past decade a quiet revolution has been taking place in the way we view the development of colorectal cancer. One of the most important seeds for this change has been the recognition of a serrated polyp pathway-type colorectal tumorigenesis associated with somatic BRAF mutation and widespread gene promoter hypermethylation as an alternative to the adenoma-carcinoma sequence.1 In this paper, we review the evidence that the development of advanced serrated polyps is a genetic trait with implications for CRC screening and prevention in the wider population. 2 HETEROGENEOUS NATURE OF COLORECTAL CANCER cLike many epithelial malignancies, colorectal cancer (CRC) is a heterogeneous disease with respect to tumour phenotype, risk factors, genetic predisposition, response to treatment and outcome and can be classified into groups with clinical relevance using molecular pathology features.3 4 Identifying genetic and environmental risk factors for subsets within this disorder is likely to improve our understanding of aetiology, and thereby contribute to CRC prevention by targeting of screening and other preventative measures to those most at risk. Hypermethylation of CpG islands in gene promoters is a well-accepted mechanism for expression silencing of tumour suppressor genes in a wide variety of human cancers. However, a distinct phenomenon associated with widespread and concordant CpG island methylation events was first described in 1999 in gastrointestinal tumours. 5CRCs with this CpG island methylator phenotype (CIMP CRC) demonstrate particular mutation profiles, proximal location in the colon, and increased mucinous and poorly-differentiated histology. 6Previous observations support the notion that CIMP tumours in the colon represent a distinct subtype of CRC.7-9 For example, using multiple CpG island markers, 295 CRC and cluster analysis, Weisenberger and colleagues were able to convincingly show that CIMP CRCs possess a discrete molecular trait which includes consistent and quantitatively-based hypermethylation of a subset of 5 CpG island markers from an original panel of 195. Subsequent validation was achieved using this novel 5-marker panel 9 in an independent series of CRC. In keeping with several previous reports, somatic BRAF mutation and CIMP were strongly associated with each other (odds ratio for association = 203), and with cancers situated in the proximal colon.9-11 CIMP CRCs included almost all sporadic cases with microsatellite instability (MSI) and, importantly, a further proportion of CRCs that were microsatellite stable (fig1). THE EPIDEMIOLOGY OF CIMP CANCERSStudies investigating the epidemiology of CIMP CRCs have also provided evidence that they represent a separate entity with their own genetic and environmental risk factors.7-9 An association with proximal location, female sex and advanced age was observed in a case-series study of 396 CRCs. 12The association with female gender however, was only evident when microsatellite unstable tumours were included. The epidemiology of CIMP CRC was ...
Escherichia coli wild-type cells form constitutively the enzyme phospho-aglucosidase A, which has a high affinity for phosphorylated aromatic ,B-glucosides and a low affinity for phosphorylated,B-methyl-glucoside. Phospho-f3-glucosidase B and f3-glucoside permease I are formed in aromatic f3-glucoside-fermenting mutants. Mutants lacking phospho-f3-glucosidases A and B have been isolated.These mutants showed a reduced rate of inducibility of the f3-glucoside permease I. The restoration of phospho-f3-glucosidase A or B activity resulted in an increased rate of induction of the ,B-glucoside permease I. The presence of the phospho-,B-glucosidases was not required for the constitutive biosynthesis of the ,B-glucoside permease. Mutants selected for growth on f,-methyl-glucoside as carbon source showed an increased level of constitutive phospho-,B-glucosidase A activity. Gene bglD, the structural gene for phospho-,B-glucosidase A, was mapped between the pyrE locus and the cluster bgl loci, whereas bglE, the regulatory site determining the hyperproduction of phospho-,B-glucosidase A, was mapped between the bgl and ilv clusters. The bglE locus appears to have a regulatory effect on the expression of the bglD gene. P-f-glucosidase A. The first type lacks P-,Bglucosidase A activity because of a mutation in the bglD locus, which is probably the structural gene for the enzyme. The second type has an increased level of constitutive P-3-glucosidase A 909 on August 5, 2020 by guest
Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-010-9408-8) contains supplementary material, which is available to authorized users.
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