Recently, a link between high levels of circulating IL-6 and hepatocellular carcinoma (HCC) has been proposed. In addition, single nucleotide polymorphisms (SNPs) in the promoter region of the IL-6 gene have been reported to be related to several inflammatory-related conditions, including cancer. The purpose of this article is: (1) to evaluate the frequencies of SNPs in the IL-6 promoter region at position -174 and IL-6 serum levels in a group of patients with HCC and underlying liver cirrhosis (LC), and compare them with a group of LC patients without HCC; (2) to determine whether a possible correlation exists between the allelic variations, IL-6 serum levels, and the risk of developing HCC. The study included 105 HCC and 95 LC patients. Genomic DNA was isolated using commercially available kits. DNA samples were typed for relevant SNPs of the IL-6 promoter region (-174 G>C, G allele being associated with higher levels of the cytokine). The Restriction Fragment Length Polymorphism (RFLP-PCR) method was used to type the SNPs. IL-6 serum levels were determined using an ultrasensitive commercially available ELISA kit. IL-6 serum levels were higher in G/G compared to C/C genotypes only in HCC (z=2; p=0.04) and G/G versus G/C (z=1.8; p<0.03). IL-6 serum levels in G carriers (G/G+G/C) were higher in HCC 4.8 (0.2-17.5) versus LC patients 2.2 (0.07-11.5) (z=2.8; p=0.004). There was no difference for genotype C/C. IL-6 serum levels in HCC correlated with G carriers (G/G+G/C) (ρ=0.25, p=0.05). A positive correlation was also found between sIL-6 levels and some parameters of liver function both in LC and in HCC patients.

Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age- and sex-matched controls. TNF-alpha (-308G/A), TGF-beta1 (+869C/T), IL-10 (-1117G/A; -854C/T; -627C/A), and IFN-gamma (874T/A) single nucleotide polymorphisms (SNPs) were identified by sequence-specific primers (SSP)-PCR or restriction fragment length polymorphism (RFLP)-PCR. Genotype or haplotype distributions for each polymorphisms were consistent with the HWE in these populations. We were unable to demonstrate differences in genotype or allele frequencies between patient and control groups. Data obtained in this study indicate that none of the cytokine SNPs studied is likely to have predisposing or protective effects on BC susceptibility. On the other hand, both positive and negative association with BC have been reported for some of the studied genotypes by different research groups. In conclusion, further studies involving larger numbers of subjects are required.

Cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), and tumor necrosis factor-α (TNF-α) are mediators of inflammation and angiogenesis; all of them are produced in liver cirrhosis (LC) and in hepatocellular carcinoma (HCC). It was proposed that there is an association between single nucleotide polymorphisms (SNPs) and HCC. These allelic variants influence the transcriptional activity of these genes, and therefore the proteins levels. The VEGF-A pathway is a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical trials in HCC. We evaluated the frequency of SNPs of COX-2, TNF-α, and VEGF-A genes in patients with HCC versus LC patients and a control group. The aim of this article was to verify the correlation between the allelic variations and the risk of developing HCC. The study included 96 HCC, 79 LC patients, and 162 healthy subjects. The evaluation of SNPs was performed by the restriction fragment length polymorphism (RFLP-PCR) method. The SNPs analyzed were: -1195 G>A of the COX-2 gene, -308 G>A of the TNF-α gene, and +936 C>T of the VEGF-A gene. Chi-square and Fisher exact tests were used for statistical analysis. Our results confirm that carriers with the C allele in the VEGF-A gene are more frequent in HCC versus LC (p=0.039), suggesting that this SNP may predispose to the development of HCC.

It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, developing colorectal cancer similar to human inflammatory bowel disease-associated neoplasia. TGF-beta1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF-beta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting a significant stimulation of tumor growth invasion and metastasis during tumor progression. We assessed association of functional polymorphisms (-1082G/A; -592C/A) and TGF-beta1 (-509C/T; +869C/T) influencing the IL-10 production to colorectal cancer risk in a case-control study of 62 patients and 124 matched controls. No significant differences were observed among cancer patients and controls for IL-10 -1082G/A; -592C/A genotype frequencies. Evaluation of odds ratios (OR) for the TGF-beta1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CT- and +869TT-positive individuals. These results suggest that the +869C allele, responsible for a Leu-->Pro substitution in the signal peptide sequence of the TGF-beta1 protein, may have a predisposing role in the development of colorectal cancer.

No abstract

Abstract. Cytochrome P450 2E1 (CYP2E1) is one of the main enzymes involved in the oxidation of ethanol and in the transformation of a number of potentially dangerous compounds. It has various polymorphic sites, one of which is a variable number tandem repeat (VNTR) polymorphism previously described in the 5'-flanking region. The aim of this study was to investigate the genotype-phenotype association between CYP2E1 VNTR polymorphisms and risky health habits in healthy subjects and to analyze the associations between these polymorphisms with drinking-and/or smoking-related cancers. We analyzed 166 healthy subjects by genotyping for the CYP2E1 VNTR polymorphism associated with drinking and/or smoking habits by the more sensitive restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method, using the NlaIV restriction enzyme. Sixty cases of pancreatic adenocarcinoma (PA) and 66 with hepatocellular carcinoma (HCC), were also genotyped. Statistical analysis was carried out to investigate the genotype-phenotype associations and to compare certain genotypes and cancer. We found 7 genotypes both in the healthy subjects and patients. The A1/A1 genotype was observed to be mainly associated with non-drinkers and -smokers (87.5 and 75.0%, respectively); moreover it was never found in the PA or HCC patients. Conversely, a weak association between A2/A3 with smokers (45.8%) and A4/A4 with drinkers (53.9%) was detected. In addition, the A4/A4 genotype was found to be significantly associated to PA [odds ratio (OR)=3.25; 95% confidence interval (CI) 1. 21-7.50]. Our data demonstrate that certain CYP2E1 VNTR genotypes are associated with drinking and/or smoking habits; consequently, they may contribute either to the decreased or increased risk of developing drinking-and/or smoking-related cancers. In particular, we hypothesize that the A1/A1 VNTR genotype may have a protective role against drinking-and/or smokingrelated cancers, and that A4/A4 may be a high-risk genotype during the early stages of cancer.

The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF-beta1 gene and -1082G/A SNP at IL-10 promoter sequence, two well-known immunosuppressive and anti-inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association. These results may be due to the pleiotropic effects of the cytokines and/or differences in haplotype combination that should be investigated to elucidate the role of TGF-beta1 and IL-10 polymorphisms in atherosclerosis.

Multiple sclerosis (MS) is a cell-mediated autoimmune disease characterized by type-1 cytokine production. Environmental and individual genetic background might influence this response particularly in cytokine gene polymorphisms. We evaluated whether polymorphisms of interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-alpha genes, which might play a role in MS pathogenesis, are associated with MS susceptibility. Genotype frequencies for all the analyzed polymorphisms were not differently distributed between cases and controls. It is reasonable to suppose that the cytokine single-nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving other functional SNPs of Th1 regulator elements such as IL-21 and IL-23.