Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer.

Polymorphisms in the 2 cell-cycle control genes Aurora A and Cyclin D1 have previously been associated with changes in the age of onset of colorectal cancer in persons harboring germline mutations in DNA mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). In this report, we have genotyped 312 individuals, who all harbored confirmed causative mutations in either hMSH2 or hMLH1, for 2 polymorphisms, one in Aurora A (T91A) and the other in Cyclin D1 (G870A). The results reveal that the previous association with the Aurora A polymorphism could not be confirmed in our larger group of HNPCC patients. The Cyclin D1 polymorphism, however, was associated with a significant difference in the age of disease onset on patients harboring hMSH2 mutations, which was not observed in hMLH1 mutation carriers. A combined analysis of the Aurora A and Cyclin D1 polymorphisms did not reveal any obvious association. In conclusion, it appears that the polymorphic variant of Aurora A does not appear to be associated with variation in colorectal cancer risk in HNPCC, whereas there is a more complex relationship between the Cyclin D1 polymorphism and disease risk in HNPCC.

Lack of association between genetic polymorphisms in cytokine genes and disease expression in patients with hereditary non-polyposis colorectal cancer.

OBJECTIVE: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in DNA mismatch repair (MMR) genes and is characterized by familial aggregations of early-onset epithelial cancers. Inflammatory cells produce an attractive environment for tumour growth since reactive oxygen and nitrogen species generated by inflammatory cytokine induction can cause damage to DNA and proteins. In this study the objective was to investigate single nucleotide polymorphisms (SNPs) in cytokine genes to assess their impact on disease expression in individuals diagnosed with HNPCC. MATERIAL AND METHODS: DNA samples from 220 participants diagnosed with HNPCC were genotyped for SNPs in IL-6, IL-1beta, TNF-alpha, IFN-gamma, IL-10, IL-4 and IL-1RN. The association between the polymorphisms and disease characteristics, i.e. affected or unaffected with colorectal cancer (CRC) and age of diagnosis of CRC, was tested with the Pearson chi2 test and by Kaplan-Meier survival analysis. RESULTS: There was no significant difference between CRC patients and unaffected MMR gene mutation carriers for any of the SNPs studied and the Kaplan-Meier survival analysis showed no significant difference between age of diagnosis of CRC and genotype. CONCLUSIONS: The SNPs selected for this study do not appear to modify disease expression in HNPCC. Given the complexity of the inflammatory response, the limited number of SNPs studied does not rule out the notion that other cytokine polymorphisms could act as disease modifiers of disease expression in HNPCC.

MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients.

Disease expression in hereditary nonpolyposis colorectal cancer (HNPCC) cannot be readily explained by mutation site in the respective DNA mismatch repair genes associated with this disorder. One explanation is the role of modifying genes that can either promote or prevent disease development on a background of increased risk. Two single nucleotide polymorphisms in MDM2 and TP53 have been shown to be associated with younger ages of disease onset in HNPCC (TP53) and Li-Fraumeni syndrome (MDM2). In this study 220 HNPCC patients were examined, from Australia and Poland, all characterized at the molecular level to determine the frequency of the MDM2 SNP309 T>G and to assess its influence on disease expression. The results were then pooled with the results of a previous study to assess the combined influence of the MDM2 SNP309 T>G and TP53 SNP R72P. A significant difference was observed between CRC patients and unaffected MMR gene mutation carriers over the age of 45 years (p = 0.01). The unaffected MMR gene mutation carriers over the age of 45 years who carry the G allele have a reduced risk of developing CRC. The results indicate that the MDM2 SNP309, alone or in combination with TP53 R72P, does not influence age of diagnosis of CRC in individuals with HNPCC. In conclusion, the data indicates the G allele of MDM2 SNP309 might have a protective effect on disease development in HNPCC patients and that age of diagnosis of CRC is not associated with MDM2 SNP309 or TP53 R72P either as single SNPs or combined.

Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germ-line mutations in DNA mismatch repair genes. There is considerable variation in disease expression that cannot be explained by genotype/phenotype correlation, which is likely to be the result of polymorphic modifier genes. One candidate group of modifiers is the xenobiotic clearance enzyme genes that encode CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. Alterations in these xenobiotic clearance genes can potentially influence the host response to carcinogen exposure and thereby alter cancer risk. We have investigated eight polymorphisms in xenobiotic clearance genes to assess the effect on the risk of disease in mutation positive HNPCC patients. METHODS: DNA samples from 220 mutation-positive HNPCC participants (86 Australian and 134 Polish) were genotyped for single nucleotide polymorphisms (SNP) in CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. The association between the SNPs and disease characteristics, disease expression and age of diagnosis of colorectal cancer (CRC), was tested with Pearson's chi(2) and Kaplan-Meier survival analysis. RESULTS: The HNPCC population displays a significant difference in the genotype frequency distribution between CRC patients and unaffected mismatch repair gene mutation carriers for the CYP1A1 SNP where the CRC patients harbor more of the mutant genotype. CONCLUSIONS: Evidence from this study is not conclusive, but our data suggest that the CYP1A1 influences disease expression in individuals with HNPCC.

Age of diagnosis of colorectal cancer in HNPCC patients is more complex than that predicted by R72P polymorphism in TP53.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer syndrome associated with germline mutations in DNA mismatch repair (MMR) genes. Recently a polymorphism at codon 72 (R72P) in the tumour suppressor gene TP53 has been implicated in the age of disease onset in HNPCC. In this report we have studied a large cohort of HNPCC patients to assess the impact of this polymorphism on disease expression and age of diagnosis of colorectal cancer (CRC). DNA samples from 218 HNPCC mutation positive patients from Australia and Poland were genotyped for the arginine to proline change at codon 72 in the TP53 gene. The association between the polymorphism and disease characteristics (mutation status, disease expression and age of diagnosis of CRC) was tested using Pearson's Chi-square and Kaplan-Meier survival analysis. Our study of Australian and Polish HNPCC patients does not provide evidence for an association between the Arg/Pro (GC) genotype of the R72P polymorphism and age of diagnosis of CRC. The R72P polymorphism was examined in HNPCC patients and found to be not associated with disease development in either the Australian or Polish populations. When gene mutation status (hMLH1 or hMSH2) was included in the analysis some evidence of an affect was observed. The genotyping revealed in the Australian population that the R72P polymorphism was under-represented in the hMSH2 group whereas it was over-represented in the Polish hMSH2 group. A similar trend was observed for hMLH1 in both groups but was not significant. Age of diagnosis of CRC in HNPCC patients is therefore more complex than that predicted by the R72P TP53 polymorphism alone, suggesting an inter-relationship with other genetic and/or environmental factors.

Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles.

Certain HLA-DQ alleles are known to contribute to predisposition to coeliac disease (CD). The existence of additional independent risk-modifying loci in the HLA complex is still being debated. The DR3-DQ2 haplotype has been studied most, but the evidence is conflicting. The discrepancies may stem from the absence of such an effect, insufficient statistical power to detect an effect (i.e. small studies) and/or incomplete control of linkage disequilibrium (LD) to the neighbouring DQ-loci, known to elicit a strong effect. In the present study, we aimed to undertake a statistically high-powered family-based analysis, fully controlling effects of LD between the major DQ-risk haplotypes and neighbouring candidate loci. We investigated five markers on DR3-DQ2, DR5-DQ7 and DR7-DQ2 haplotypes in 327 Norwegian and Swedish families. Our primary finding was that TNF-308A ( TNF2) was significantly associated on the DR3-DQ2 haplotype [stratum specific odds ratio (OR) = 2.40 (1.25-4.48), Pc = 0.009, where P(c) = Pn and n = number of tests performed]. Furthermore, we confirmed earlier indications that LD between TNF2 and DQA1*05-DQB1*02 on the DR3 haplotype is more strongly maintained in family-based cases than family-based controls. In conclusion, we confirmed in this study, the largest of its kind, that additional CD risk factors independent of DQ2 alleles do exist on the DR3 haplotype.