Advance Access publication April 30, 2008 (original) (raw)
Related papers
Interleukin promoter polymorphisms and prognosis in colorectal cancer
Carcinogenesis, 2008
There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five singlenucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A 1 B than with stages C 1 D (P trend 5 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time. 10) and one customized assay: IL6-174G/C (rs1800795, primers: TGAC-GACCTAAGCTGCACTTTTC, GGGCTGATTGGAAACCTTATTAAGA, probes: VIC-TCTTGCGATGCTAAA, FAM-TCTTGCCATGCTAAA, the SNP position is underlined). For TaqMan polymerase chain reaction, 5 ng of genomic DNA was analyzed in a total volume of 5 ll with an ABI PRISM 7900
Regulatory Cytokine Gene Polymorphisms and Risk of Colorectal Carcinoma
Annals of the New York Academy of Sciences, 2006
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-1) 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 diseaseassociated neoplasia. TGF-1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF-1 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; 98 CRIVELLO et al.: CYTOKINE POLYMORPHISMS AND COLON CANCER RISK 99 -592C/A) and TGF-1 (-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-1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CTand +869TT-positive individuals. These results suggest that the +869C allele, responsible for a Leu→Pro substitution in the signal peptide sequence of the TGF-1 protein, may have a predisposing role in the development of colorectal cancer.
Genetic Variants of the IL2 Gene Related to Risk and Survival in Patients With Colorectal Cancer
Anticancer Research, 2019
Background: Interleukin 2 (IL2) is a significant factor activating T-cell-mediated immune response by stimulation of natural killer cells, T-cells and in development of regulatory T (Treg) cells. Recent studies have that IL2 participates in cancer development by modifying the local immune response. Based on the suggested role of the single nucleotide polymorphisms (SNPs) rs2069762, rs6822844 and rs11938795 of IL2 in the pathogenesis of certain diseases, the relationship of these SNPs with clinicopathological variables and their possible implication for prognosis and disease outcome were evaluated in a cohort of Swedish patients with colorectal cancer (CRC). Materials and Methods: TaqMan SNP genotype assays based on polymerase chain reaction were used for analysis of the IL2 SNPs in 467 patients with CRC and 467 healthy controls. Expression analysis of IL2 in plasma and CRC tissue was also performed. Results: The allelic variants T in rs11938795 and G in rs6822844 were significantly associated with a higher risk of CRC. Kaplan-Meier analysis showed that cancer-specific survival was worse for individuals with C allele for rs2069762 with stage II CRC and with T allele for rs6822844 with stage III CRC. Conclusion: SNPs rs2069762, rs6822844 and rs11938795 of the IL2 gene may be helpful as prognostic biomarkers in the follow-up and management of the patients. Colorectal cancer (CRC) is one of the most common types of malignancy worldwide (1). The pathogenesis of CRC is still not fully understood and the molecular mechanisms underlying tumor progression and metastasis are unclear. Cancer-related inflammation appears to be a hallmark of CRC and cytokines play a central role in the carcinogenic process since they are key regulators of immune responses (2, 3). Several interleukins (ILs) modulate intestinal tumor development, differentiation, and inflammatory and antiinflammatory responses. IL2 secreted by T-helper type 1 (Th1) cells is an important factor in activating T-cellmediated immune responses and stimulating the proliferation and differentiation of B-cells and natural killer cells. In addition, IL2 is involved in development of regulatory Tcells (Tregs) (4, 5). Genetic variation, such as single nucleotide polymorphisms (SNPs), of inflammatory genes is suggested to play a role in the risk of CRC and survival of patients (6, 7). Polymorphic variants within the IL2/IL21 region at 4q27 have been discovered to be related to multiple diseases. The SNP rs6822844 is positioned in the IL2/IL21 intergenic region and is associated with multiple autoimmune diseases (8, 9). SNP rs11938795 is located in the same IL2/IL21 block and is related to Crohn's disease (10). Another SNP of the IL2 gene, rs2069762, is located in the promoter region and is implicated in increased susceptibility to gastric (11), oral (12), nasopharyngeal (13) and breast cancer (14). A hot topic in CRC research is the search for clinically applicable biomarkers that can aid in diagnosis, prognostication and prediction of treatment response (15, 16). CRC staging is primarily based on the tumor-nodemetastasis (TNM) system of the American Joint Committee on Cancer (AJCC) classification system (17). Stage II CRC is generally considered as having a good prognosis, but a 4933 This article is freely accessible online.
The …, 2008
The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P ¼ 0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P ¼ 0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.
Polymorphisms within inflammatory genes and colorectal cancer
2006
Background: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain).
Polish Journal of Surgery, 2011
Colorectal carcinoma is one of the leading causes of death from cancer amongst adults. Considering its molecular background, cytokines are the key component of the inflammatory microenvironment of these tumors. Investigations that enable better understanding of colorectal cancer concerning the molecular level, may provide important tools for genetic screening of disease high-risk groups, as well as molecular diagnostics for the non-invasive detection of cancer in its early stages.THE AIM OF THE STUDY was to evaluate the association between colorectal cancer and the -1112 C/T single nucleotide polymorphism (SNP) of the interleukin-13 gene. MATERIAL AND METHODS. The study group comprised 150 cancer patients and 170 healthy subject genotypes from the Polish population. Analysis was performed by PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS. We showed that the CT genotype is connected with a higher risk of colon cancer occurrence (OR 2.51; 95% CI 1.57-4.02; p < 0.0001). We also correlated the polymorphic variants of the IL-13 gene with the clinical characteristics of colorectal cancer patients. We observed no association between the investigated polymorphism and colorectal cancer progression, evaluated by tumor stage, as well as lymph node metastasis. CONCLUSIONS. The presented study suggested the possibility of a connection between the IL-13 gene polymorphism (-1112 C/T) and colorectal cancer risk in the Polish population.
Pharmacogenetics and Genomics, 2009
Purpose Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage II colon cancer who are more likely to benefit from adjuvant chemotherapy. Interleukin 1 beta (IL1B) and interleukin 1 receptor antagonist (IL1RN) have been shown to play a critical role in the early onset of tumor-associated angiogenesis. In this study, we tested whether eight functionally significant polymorphisms within six genes of the angiogenesis pathway [IL1B, IL1RN, vascular endothelial growth factor A (VEGFA), VEGF receptor 2, interleukin-8, cyclooxygenase-2] will predict the risk of tumor recurrence in stage II colon cancer patients treated with 5-fluorouracil based adjuvant chemotherapy. Experimental design Blood samples were obtained from 109 patients with stage II colon cancer at the University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism protocols. Results Patients harboring the IL1RN/IL1B 1-T-C (IL-1RN variable number tandem repeats (VNTR)/IL1B C + 3954T/ C-511T) haplotype were at greatest risk of developing tumor recurrence [relative risk (RR): 2.72, 95% confidence interval (
Immunologic Research, 2018
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Genetic variations in cytokine genes and their receptors lead to the severity of the disease. The interleukin-1 receptor antagonist (IL1RN) is a cytokine that inhibits interleukin-1 (IL-1) activity by binding to IL-1 receptors. Also, interleukin-4 (IL-4) is an anti-inflammatory cytokine that can play an important role in several cancers. The present case-control study was aimed to evaluate the association of IL-4 and IL1RN VNTR polymorphisms with the susceptibility to CRC in a sample of Iranian population provided by the Research Center for Gastroenterology and Liver Disease at Taleghani Hospital, Tehran. A total of 123 patients diagnosed with CRC and 152 healthy controls were recruited in the present study. Genomic DNA was extracted by salting out method from whole blood and genotyping of IL1RN and IL-4 VNTR polymorphisms were determined by PCR-based technology. Our study manifested the frequency of 1/2 and 2/4 genotypes of IL1RN 68bp VNTR polymorphism are significantly different between both groups (p = 0.0001 and p = 0.01 respectively). However, we could not find any correlation between IL-4 VNTR polymorphism and CRC cancer. It seems that 1/2 and 2/4 genotypes of IL1RN are correlated with CRC susceptibility in our population, although, more studies are needed to confirm our results.
Interleukin-4 and interleukin-4 receptor polymorphisms and colorectal cancer risk
European Journal of Cancer, 2007
Interleukin-4 (IL-4) and interleukin-4 receptor (IL-4R) modulate inflammation and are associated with the colorectal adenoma-carcinoma progression and the metastatic capacity. IL-4 also causes a dose-dependent reduction of proliferation in colorectal cancer cells. The aim of the study was to evaluate whether genetic variants within IL4 and IL4R could affect the individual risk to develop colorectal cancer. We genotyped all the polymorphisms coding for an aminoacidic change in IL4R and we used a haplotype-tagging SNP approach for IL4. We carried out a case-control association study by genotyping, with the 5 0 nuclease assay, two common SNPs within IL4 (À588C > T, Ex1-168G > A) and five SNPs within IL4R (I75V, C431R, S436L, S503P, Q576R) in 377 cases of colorectal cancer and 326 controls from Spain. No statistically significant association between the SNPs investigated and colorectal cancer risk was found, as main effects. When the sub-analyses were carried out, the homozygotes for IL4 À588C > T or for Ex1-168G > A showed an increased risk for colon cancer only, with the odds ratios of 4 (95% CI 0.97-16.6; P-interaction = 0.016 and 4.66 (95% CI 1.16-18.77; P-interaction = 0.023), respectively. Moreover, women showed a significant increased risk associated to the IL4 rare alleles and this was clearly greater than that in men (for Ex1-168G > A: OR = 1.96; 95% CI = 1.11-3.47; P-interaction = 0.006). However, when sub-groups are analysed, the findings should be taken with caution for the weakening of the statistical power.