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The ethiology of colon cancer is largely dependent on inflammation driven oxidative stress. The analysis of 8-oxodeoxyguanosine (8-oxodGuo) level in leukocyte DNA of healthy controls (138 individuals), patients with benign adenomas (AD, 137 individuals) and with malignant carcinomas (CRC, 169 individuals) revealed a significant increase in the level of 8-oxodGuo in leukocyte DNA of AD and CRC patients in comparison to controls. The counteracting mechanism is base excision repair, in which OGG1 and PARP-1 play a key role. We investigated the level of PARP-1 and OGG1 mRNA and protein in diseased and marginal, normal tissues taken from AD and CRC patients and in leukocytes taken from the patients as well as from healthy subjects. In colon tumors the PARP-1 mRNA level was higher than in unaffected colon tissue and in polyp tissues. A high positive correlation was found between PARP-1 and OGG1 mRNA levels in all investigated tissues. This suggests reciprocal influence of PARP-1 and OGG1 on their expression and stability, and may contribute to progression of colon cancer. PARP-1 and OGG1 proteins level was several fold higher in polyps and CRC in comparison to normal colon tissues. Individuals bearing the Cys326Cys genotype of OGG1 were characterized by higher PARP-1 protein level in diseased tissues than the Ser326Cys and Ser326Ser genotypes. Aforementioned result may suggest that the diseased cells with polymorphic OGG1 recruit more PARP protein, which is necessary to remove 8-oxodGuo. Thus, patients with decreased activity of OGG1/polymorphism of the OGG1 gene and higher 8-oxodGuo level may be more susceptible to treatment with PARP-1 inhibitors.

Background A characteristic feature of malignant cells, such as colorectal cancer cells, is a profound decrease in the level of 5-hydroxymethylcytosine, a product of 5-methylcytosine oxidation by TET enzymes. Recent studies showed that ascorbate may upregulate the activity of TET enzymes in cultured cells and enhance formation of their products in genomic DNA. Methods The study included four groups of subjects: healthy controls (n = 79), patients with inflammatory bowel disease (IBD, n = 51), adenomatous polyps (n = 67) and colorectal cancer (n = 136). The list of analyzed parameters included (i) leukocyte levels of epigenetic DNA modifications and 8-oxo-7,8-dihydro-2′-deoxyguanosine, a marker of oxidatively modified DNA, determined by means of isotope-dilution automated online two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry, (ii) expression of TET mRNA measured with RT-qPCR, and (iii) chromatographically-determined plasma concentrations of retinol, alpha-tocopherol and ascorbate. Results Patients from all groups presented with significantly lower levels of 5-methylcytosine and 5-hydroxymethylcytosine in DNA than the controls. A similar tendency was also observed for 5-hydroxymethyluracil level. Patients with IBD showed the highest levels of 5-formylcytosine and 8-oxo-7,8-dihydro-2′-deoxyguanosine of all study subjects, and individuals with colorectal cancer presented with the lowest concentrations of ascorbate and retinol. A positive correlation was observed between plasma concentration of ascorbate and levels of two epigenetic modifications, 5-hydroxymethylcytosine and 5-hydroxymethyluracil in leukocyte DNA. Moreover, a significant difference was found in the levels of these modifications in patients whose plasma concentrations of ascorbate were below the lower and above the upper quartile for the control group. Conclusions These findings suggest that deficiency of ascorbate in the blood may be a marker of its shortage in other tissues, which in turn may correspond to deterioration of DNA methylation-demethylation. These observations may provide a rationale for further research on blood biomarkers of colorectal cancer development.

Nutritional status assessment is an important part of preoperative patient evaluation, but the standard anthropometric parameters do not appear to be adequate. To determine the changes in the values of bioelectrical impedance analysis (BIA) parameters in patients 3 months after undergoing surgery for colorectal cancer (CRC). BIA and nutritional status assessment parameters were determined in 80 patients prior to undergoing surgery for CRC. The results 3 months after surgery for 64 of those patients were then compared with their initial assessments. According to standard WHO ranges, 54% of the patients were diagnosed as being overweight and 29% as obese. The percentage of patients categorized as obese amounted to 56% when this was defined as high fat mass. Moderate sarcopaenia, defined as a low skeletal muscle index (SMI) or low percentage of skeletal muscle mass, was diagnosed in 21% and 29% of patients, respectively. Patients with postoperative weakness that made it impossible for them to attend the control visit had a lower preoperative skeletal muscle mass ( = 0.01) and SMI value ( = 0.001). Parameters of BIA did not discriminate patients with postoperative complications, which occurred in 23% of individuals enrolled. A significant proportion of the patients undergoing surgery for CRC were overweight or obese, which could mask the sarcopaenia that presented in 21-29% of them. Sarcopaenia was the only parameter predictive of a postoperative decrease in performance status.

Background Active demethylation of 5-methyl-2′-deoxycytidine (5-mdC) in DNA occurs by oxidation to 5-(hydroxymethyl)-2′-deoxycytidine (5-hmdC) and further oxidation to 5-formyl-2′-deoxycytidine (5-fdC) and 5-carboxy-2′-deoxycytidine (5-cadC), and is carried out by enzymes of the ten-eleven translocation family (TETs 1, 2, 3). Decreased level of epigenetic DNA modifications in cancer tissue may be a consequence of reduced activity/expression of TET proteins. To determine the role of epigenetic DNA modifications in colon cancer development, we analyzed their levels in normal colon and various colonic pathologies. Moreover, we determined the expressions of TETs at mRNA and protein level. The study included material from patients with inflammatory bowel disease (IBD), benign polyps (AD), and colorectal cancer (CRC). The levels of epigenetic DNA modifications and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) in examined tissues were determined by means of isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS). The expressions of TET mRNA were measured with RT-qPCR, and the expressions of TET proteins were determined immunohistochemically. Results IBD was characterized by the highest level of 8-oxodG among all analyzed tissues, as well as by a decrease in 5-hmdC and 5-mdC levels (at a midrange between normal colon and CRC). AD had the lowest levels of 5-hmdC and 5-mdC of all examined tissues and showed an increase in 8-oxodG and 5-(hydroxymethyl)-2′-deoxyuridine (5-hmdU) levels. CRC was characterized by lower levels of 5-hmdC and 5-mdC, the lowest level of 5-fdC among all analyzed tissues, and relatively high content of 5-cadC. The expression of TET1 mRNA in CRC and AD was significantly weaker than in IBD and normal colon. Furthermore, CRC and AD showed significantly lower levels of TET2 and AID mRNA than normal colonic tissue. Conclusions Our findings suggest that a complex relationship between aberrant pattern of DNA epigenetic modification and cancer development does not depend solely on the transcriptional status of TET proteins, but also on the characteristics of premalignant/malignant cells. This study showed for the first time that the examined colonic pathologies had their unique epigenetic marks, distinguishing them from each other, as well as from normal colonic tissue. A decrease in 5-fdC level may be a characteristic feature of largely undifferentiated cancer cells.

Background CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. Results The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Conclusion Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

The active DNA demethylation mechanism involves 5-methylcytosine (5-mCyt) enzymatic oxidation with the subsequent formation of 5-hydroxymethylcytosine (5-hmCyt), which can be further oxidized to 5-formylcytosine (5-fCyt) and 5-carboxylcytosine (5-caCyt). The products of active DNA demethylation are released into the bloodstream and eventually also appear in urine. We used online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) to compare DNA methylation marks and 8-oxo-2′-deoxyguanosine (8-oxodG) in colorectal cancer and pre-cancerous condition in urine. The study included four groups of subjects: healthy controls, patients with inflammatory bowel disease (IBD), persons with adenomatous polyps (AD), and individuals with colorectal cancer (CRC). We have found that the level of 5-fCyt in urine was significantly lower for CRC and polyp groups than in the control group. The level of 5-hmCyt was significantly higher only in the CRC group compared to the control (2.3 vs. 2.1 nmol/mmol creatinine). Interestingly, we have found highly statistically significant correlation of 5-hydroxymethyluracil with 5-hydroxymethylcytosine, 5-(hydroxymethyl)-2′-deoxycytidine, 5-(hydroxymethyl)-2′-deoxyuridine, and 5-methyl-2′-deoxycytidine in the CRC patients’ group.

The continued identification of new low-penetrance genetic variants for colorectal cancer (CRC) raises the question of their potential cumulative effect among compound carriers. We focused on 6 SNPs (rs380284, rs4464148, rs4779584, rs4939827, rs6983267, and rs10795668), already described as risk markers, and tested their possible independent and combined contribution to CRC predisposition. Material and Methods. DNA was collected and genotyped from 2330 unselected consecutive CRC cases and controls from Estonia (166 cases and controls), Latvia (81 cases and controls), Lithuania (123 cases and controls), and Poland (795 cases and controls). Results. Beyond individual effects, the analysis revealed statistically significant linear cumulative effects for these 6 markers for all samples except of the Latvian one (corrected P value = 0.018 for the Estonian, corrected P value = 0.0034 for the Lithuanian, and corrected P value = 0.0076 for the Polish sample). Conclusions. The significant linear cumulative effects demonstrated here support the idea of using sets of low-risk markers for delimiting new groups with high-risk of CRC in clinical practice that are not carriers of the usual CRC high-risk markers.

Background: Adipocytokines have been proposed as factors mediating associations between obesity and inflammation in patients with colorectal cancer (CRC). Thus, the aim of this study was to determine the clinical relationships between blood concentrations of leptin (LEP), adiponectin (ADP), and tumor necrosis factor alpha (TNF-alpha) and the outcomes measured in patients with CRC undergoing surgery. Patients and Methods: History, body composition, and blood concentrations of LEP, ADP, and TNF-alpha were determined in 107 patients undergoing surgery due to CRC. The patients were followed up for 619.72 ± 371.65 days. Results: Compared to patients with stage II CRC, individuals with clinical stage I CRC had significantly lower ADP and higher TNF-alpha blood concentrations. We found significant correlations between the clinical stage of CRC (early vs. localized vs. metastatic) and the following: crude blood ADP concentration (R = 0.25; p = 0.015), ADP-to-TNF-alpha ratio (R = 0.31; p = 0.002), and ADP when indexed to body surface area (R = 0.25; p = 0.008) and to fat mass (R = 0.25; p = 0.016). The risk of death during the long-term follow-up period was independently related to the clinical stage of CRC, impairment of the patient’s functional status, and higher blood carcinoembryonic antigen concentration. In Kaplan-Meier survival analysis, patients with blood LEP concentrations adjusted to a visceral adipose tissue score of ≥0.47 had a significantly better likelihood of surviving than their counterparts. Conclusions: In patients with CRC undergoing surgery, blood ADP and TNF-alpha concentrations were associated with the clinical stage of the cancer, likelihood of radical tumor excision, occurrence of nonsurgical postoperative complications, and long-term survival, which suggests the role of dysregulation in the endocrine function of adipose tissue in response to the neoplasmatic process.

CHEK2 gene is located on chromosome 22q12.1. and encodes the human analogue of the yeast checkpoint kinases Cds1 and Rad 53. Activation of CHEK2 in response to DNA damage prevents the cell from entering into mitosis. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein IVS2+1G>A in exon 3 and 1100 del C in exon 10, the other, I157T is a missense substitution of an isoleucine for a threonine in exon 3. A single founder allele of the CHEK2 has been associated with predisposition to breast and prostate cancer in North America and Europe. CHK2 alterations are associated with an increased risk of thyroid, prostate, breast, colon and kidney cancer in Polish population. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin, the del 5395 also confers an increased risk of prostate cancer in Polish men. The CHEK2 is therefore a good candidate for a multisite cancer susceptibility gene. We reasoned, that CHEK2 alterations ought to be investigate in gastric cancer cases, too.

Results of studies performed in our center point at DNA changes of many cancer (mostly moderate) susceptibility genes. Association of \"weak\" mutations and polymorphism of many genes and additional influence of environmental factors can significantly increase the risk of cancer development. The preliminary studies performed in our department indicate, that increased risk of gastric cancer may be related to mutation in NOD2 and CHK2 genes predisposing to cancers of many organs. The CHEK2 gene encodes checkpoint kinase 2 (Chk2), it acts as a tumor suppressor whose functions are central to the induction of cell cycle arrest and apoptosis by DNA damage. Results of studies performed in our center indicate that the frequency of the IVS2+1GA alteration was significantly increased in a group of 658 consecutive patients, especially in those under 50 years of age (OR=5.332, p=0.0174). I157T was over-represented in the group of familial gastric cancer patients, particularly in patients diagnosed at less than 50 years of age (OR=3.687, p=0.0011) and females. The specific group of intestinal and mixed histopathological subtype occurs more frequently (OR=1.671) in consecutive carriers of I157T mutation. Recently, the NOD2/CARD15, gene located on chromosome 16q12, has been associated with Crohns disease. It is believed to play a role both in intracellular recognition of lipopolysaccharides (LPS) typical of Gram negative bacteria and subsequent activation of NFkB. 3020insC NOD2 mutation causes an increased risk of developing chronic inflammatory diseases of the gastrointestinal tract and colorectal cancer in their course. In light of recent studies, in fact 3020insC mutation predisposes to cancers of many organs, including breast, ovarian, lung. Studies conducted in our center in the group of 103 patients with a family history of gastric cancer, have shown that NOD2 3020insC carriers in persons over 50 y of age more than doubled (OR=2.479, p=0.022) and among women almost 3-fold increased risk. In addition, NOD2 R702W alteration occurred almost three times more frequently (OR=2.816, p=0.0121) in the group of 241 consecutive patients with gastric cancer diagnosed before 50 years of age and over 2-times frequently (OR=2.268, p=0.0371) in gastric cancer selected histopathologically as intestinal type according to Lauren. There are a large number of reports describing the relationship between changes in the gene TP53, particularly polimomorfizm Arg72Pro, and risk of gastric cancer. Many researchers have found links between gene polymorphism of Interleukin-1, and the risk of stomach cancer. Gene polymorphism of angiotensin converting enzyme ACE, was recently linked with the pathogenesis and development of human cancers. Research Ebert MP, et al. conducted in a group of 88 patients shows that the insertion / deletion ACE gene may be associated with the development of early gastric cancer in the German population. In the Japanese population genetically distant, however, found no relationship between gastric cancer and ACE gene polymorphism). Sentences on the ACE polymorphism and risk of stomach cancer researchers are divided among different centers. XRCC1 gene is part of composite protein complex containing the ss-polymerase DNA ligase I and PARP (polymerase poly (ADP-ribose). This multi-unit complex is involved in DNA repair pathway. T. Poplawski et al. indicate that the variant Gln / Gln XRCC1 gene polymorphism Arg399Gly occurred more frequently in patients with gastric cancer and family burden (OR=2.04, 95% CI=1,27-3,29) and the results obtained from studies in the group of 152 patients with a family history of gastric cancer suggest that gene XRCC1 399Gln allele may be considered a marker of gastric cancer. In terms of predisposition to gastric cancer has also been studied recently LAPTM4B gene associated with a genetic predisposition to liver cancer, having LAPTM4B alleles * 1 and LAPTM4B * 2. The risk of stomach cancer was increased 1.819 times in patients with genotype * 1 / 2 (CI=1.273-2.601) and 2.387 times in patients with genotype * 2 / 2 LAPTM4B (CI=1.195-4.767) compared with genotype * 1 / first. These studies indicate that allele * 2 LAPTM4B may be one of the genetic factors of gastric cancer. Further studies of newly described mutation moderately increased risk of stomach cancer may allow to estimate the real risk of gastric cancer associated with these mutations in the Polish population.