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Abstract Background Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination. Methods We mapped mitotic recombination boundaries ("breakpoints") between the centromere (~50 Mb) and APC (~112 Mb) in early colorectal tumours. Results Breakpoints were non-random, with the highest frequency between 65 Mb and 75 Mb, close to a low copy number repeat region (68–71 Mb). There were, surprisingly, few breakpoints close to APC, contrary to expectations were there constraints on tumorigenesis caused by uncovering recessive lethal alleles or if mitotic recombination were mechanistically favoured by a longer residual chromosome arm. The locations of mitotic and meiotic recombination breakpoints were correlated, suggesting that the two types of recombination are influenced by similar processes, whether mutational or selective in origin. Breakpoints were also associated with higher local G+C content. The recombination and gain/deletion breakpoint maps on 5q were not, however, associated, perhaps owing to selective constraints on APC dosage in early colorectal tumours. Since polymorphisms within the region of frequent mitotic recombination on 5q might influence the frequency of LOH, we tested the 68–71 Mb low copy number repeat and nearby tagSNPs, but no associations with colorectal cancer risk were found. Conclusion LOH on 5q is non-random, but local factors do not greatly influence the rate of LOH at APC or explain inter differential susceptibility to colorectal tumours.

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]