Background: Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a threecenter collaborative study including two U.K. casecontrol cohorts (Sheffield and Leeds) and a U.S. casecontrol study of CRC cases from high-risk Utah pedigrees. Methods: Our combined resource included 1,092 CRC case subjects and 1,060 age-and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related casecontrol resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site.

Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (293G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 293A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG 5 3.30, 95% CI 1.46-7.47, n 5 1392, p 5 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG51.68, 95% confidence interval (CI) 1.00-2.83, n 5 1,518, p 5 0.05, proximal vs distal CRC). These findings suggest that the MLH1 293G>A polymorphism defines a low penetrance risk allele for CRC. ' 2008 Wiley-Liss, Inc.Key words: MLH1; mismatch repair; colorectal; polymorphism; proximal; promoter; dna repair; cancer MLH1 and MSH2 are components of the DNA mismatch repair (MMR) system, which recognises and repairs mismatches in DNA that occur during replication. 1 Rare constitutional mutations in MLH1, MSH2 and other genes are responsible for the autosomal dominant disorder hereditary nonpolyposis colorectal cancer (HNPCC), 2,3 where loss of MMR predisposes to colorectal cancer (CRC) with high penetrance. Loss of MMR can also develop somatically and occurs in 15-20% of all CRC. 4 Loss of MMR frequently involves MLH1 gene promoter silencing and concomitant loss of protein expression, which gives rise to CRC predominantly in the proximal colon. In addition to rare constitutional mutations, MMR genes also contain common single nucleotide polymorphisms (SNP) which can predispose to nonfamilial CRC with low to moderate penetrance, 5-7 suggesting an important contribution of common genetic variants to the burden of CRC in the general population.In view of the importance of MLH1 in colorectal carcinogenesis, we examined the association between a potentially functional SNP in MLH1 (dbSNP ID:rs1800734) and risk of CRC. The MLH1 293G>A polymorphism is located in the core promoter of MLH1, 93 bases upstream of the transcription start site in a region that is required for maximal transcriptional activity. 8,9 Polymorphic variation in this region is predicted to affect MLH1 protein expression. Indeed, site-directed mutagenesis of the adenine residue 2 bases downstream of the 293G>A polmorphism (position-91) reduces promoter activity by 75%. 9 These observations suggest that the MLH1 293G>A polymorphism might affect risk of CRC. Consistent with this hypothesis, the MLH1 293A variant has been associated with an increased risk of developing hyperplastic colonic polyps in smokers, 10

Drainage of the pleura and mediastinum after cardiac surgery is routinely achieved with rigid, wide-bore plastic drains. 1 Although these drains are effective, they are also painful, particularly during removal, 2 and they may cause damage to bypass grafts, impair ventilation, and cause cardiac arrhythmias. 3 Flexible fluted silicone drains may be just as effective. 4 Because of the fluted design, smaller sizes can be used without any reduction in the effective drainage capacity. The small size and flexibility may cause less pain, interfere less with the heart and surrounding structures, and result in fewer drain site infections. To investigate these potential benefits and to establish the efficacy of these drains, we designed a prospective, randomized trial that compared the two types of drain.

Polymorphisms in double-strand DNA repair gene XRCC2 may play an important role in colorectal cancer (CRC) etiology, specifically in disease subtypes. Associations of XRCC2 variants and CRC were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases, 1,422 controls). The 14 variants studied were tagging-SNPs selected from HapMap/NIEHS data, supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple CRC groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta analyses of the total resource that includes family-based data. Similar to reports of CRC and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (OR 2.1, 95%CI 1.3-3.3; pchisq. =0.0006) versus controls, with the largest risk found for female rectal cases (OR 3.1, 95%CI 1.6-6.1; pchisq. =0.0006). This difference was significantly different to that for proximal and distal colon cancers (pchisq. =0.02). Our investigation supports a role for XRCC2 in CRC tumorigenesis, conferring susceptibility to rectal tumors.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.