Search

Background: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5′, 3′, and exon 9 of the adenomatous polyposis coil (APC) gene. These mutations probably encode a limited amount of functional APC protein. Methods and results: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5′ Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes (‘third hits’) in some polyps. We found that the ‘third hit’ probably initiated tumorigenesis. Somatic mutation spectra were similar in 5′ and 3′ mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, ‘third hits’ were more common. Most ‘third hits’ left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele. Conclusions: We propose that mutations, such as nt4661 insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need ‘three hits’ however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele. [ABSTRACT FROM AUTHOR]

Introduction may be important for colorectal cancer risk because of its role in cell growth and differentiation. High serum levels have been associated with increased risk of colorectal cancer. Variations in these serum levels have been associated with a CA repeat microsatellite 1 kilobase upstream of the transcription start site. We sought to determine the association of germline variation of the gene with colorectal cancer predisposition by performing a large case-control study. Methods Genescan 500 was used to differentiate alleles of the microsatellite among 2143 colorectal cancer cases (enriched for family history) and 1715 controls from the CORGI (COloRectal Gene Identification) study, with subsequent 100% confirmation of about 5% of genotypes by direct sequencing. Associations of genotypes with the following clinicopathological features were tested: sex; site of tumour; Dukes stage; age of onset; presence of adenomas. Using genotype data obtained from the Hap550 platform by colleagues plus the genotypes at the insertion/deletion, we reconstructed haplotype blocks around the gene in the controls using 68 tagging SNPs. Results All the alleles confer increased risk for colorectal neoplasia except ‘192' (192 copies of CA repeat), which is a protective allele (allelic OR for ‘192' =1.199; 95% CI 1.09 to 1.32; p = 0.000152). The population attributable risk (PAR) for the risk ‘allele' (ie, where ‘X'=not ‘192') is 2.94%. The risk alleles occurred more frequently in more advanced Dukes' stage tumours (p=0.039, χ). Several SNPs in close linkage disequilibrium with are also significantly associated with colorectal neoplasia risk. Conclusion This study demonstrates a novel association of microsatellite with colorectal cancer risk. The association is stronger with advanced stage colorectal cancers, and in colonic rather than rectal cancers. This microsatellite is in linkage disequilibrium with other significant SNPs in the promoter region of this gene. [ABSTRACT FROM PUBLISHER]

Introduction Progressive loss of cell cycle control is an important feature on the adenoma-carcinoma sequence of colorectal cancer. Cyclin-dependent kinase inhibitor 1A (/ is an important target of the TGFβ signalling pathway, and it is commonly under-expressed as colorectal neoplasia develop. The aim of this study was to identify low penetrance germline variation in this gene which predisposes individuals to colorectal cancer. Methods Variation in the coding region of was determined in fifty colorectal cancer cases with a strong family history and 50 controls were tested using the Lightscanner and direct sequencing. 15 tagging SNPs around were typed in the CORGI cases and controls as part of a genome-wide analysis using the Illumina Hap550 platform in 930 cases and 960 controls performed by colleagues (Tomlinson et al 2007). Allele-specific expression of the gene was examined using quantitative reverse transcriptase PCR linked to SNPs in an upstream promoter region. Results A novel amino-acid changing variant Phe22Leu was identified in a single colorectal cancer patient. Six patients were identified in the case group and 5 in the control group with Arg31Ser. In the association study the two most significant SNPs lie in an upstream promoter region and are in linkage disequilibrium, both are risk alleles for colorectal cancer (OR 1.13; 95% CI 1.06 to 1.2). There were significant differences in expression between and the controls in 94 samples (p=0.037, Student's t test), demonstrating linkage of these upstream polymorphisms to allele-specific expression of . Conclusion Rare variants of / are an infrequent cause of predisposition to colorectal neoplasia. A promoter region upstream of the is associated with prediposition to colorectal neoplasia, and is linked to allele-specific expression of this gene. [ABSTRACT FROM PUBLISHER]