Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.

Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.

Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma.

Death-associated protein kinase (DAPK) has pro-apoptotic functions and participates in various apoptotic systems. DAPK acts as a tumor suppressor, and its inactivation by promoter hypermethylation has been frequently observed in various human cancers. As alterations of pro-apoptotic genes might cause instability in the balance of cell-turnover during chronic inflammatory processes, epigenetic silencing of DAPK might be involved in the carcinogenesis of ulcerative colitis-associated carcinoma (UCC). To evaluate the role of DAPK in the inflammation-driven carcinogenesis of ulcerative colitis (UC), we analyzed promoter hypermethylation and protein expression of DAPK using methylation-specific PCR and immunohistochemistry in 43 UCCs and paired UC-background mucosa, as well as in UC-background mucosa of 50 patients without UCC. The frequency of methylation of DAPK in UCCs was low (27.6%) compared to overall non-neoplastic UC-background mucosa (48.3%; p=0.02) and sporadic colorectal carcinoma (57.4%, p=0.019). The difference in the methylation frequency in UC-background mucosa in patients without UCC (54.2%), compared to those with UCC (40.0%), was not significant (p=0.141). Promoter methylation correlated significantly with decreased DAPK protein expression (p<0.001) and severity of inflammatory activity (p=0.024). In unmethylated UC-background mucosa, DAPK protein expression increased with activity of UC-associated inflammation, suggesting a protective role of the pro-apoptotic DAPK during the chronic inflammatory process of UC. Thus, inactivation of DAPK by promoter hypermethylation might be crucial for accumulation of DNA damage in inflamed mucosa of UC, and might therefore contribute to the initiation of the neoplastic process and development of UC-associated carcinoma.

Anal cancer in renal transplant patients.

PURPOSE: A comprehensive literature review was performed to examine the prevalence of anal cancer, anal intraepithelial neoplasia (AIN) and anal human papillomavirus (HPV) infection in renal transplant recipients who are at risk of anal cancer due to iatrogenic immunosuppression. METHODS: Pertinent articles were identified from searches performed on the National Center for Biotechnology Information database using the following keywords: anal cancer, AIN, screening, renal transplant (or kidney transplant), organ transplant recipients and post-transplant malignancies. RESULTS: The prevalence of AIN is 20% in renal transplant patients. The prevalence of anal HPV infection in established transplant patients is 47%, and the prevalence of anal HPV infection in new transplant patients is 23%. The relative risk for anal cancer in renal transplant patients is 10. CONCLUSIONS: As compared to HIV-positive male patients who practise anal intercourse, renal transplant patients showed a modest rise in relative risk for anal cancer. Screening programmes to detect AIN in HIV-positive patients who practise anal intercourse have been introduced on a preliminary basis in sexual health clinics in the US and may become standard practise in this population. The case for screening in renal transplant patients is unclear and would merit further investigation, especially with reference to the prevalence of anal HPV infection in this population. It may transpire that renal transplant patients would benefit more from HPV prophylaxis rather than screening for AIN.