The significance of DNA methylation profile in metastasis-related genes for the progression of colorectal cancer.

DNA methylation, an epigenetic modification plays a role in the pathogenesis of colorectal cancer (CRC). CRC cases, both sporadic and familial, are often characterized by abnormal pattern of the cytosine methylation in CpG dinucleotides in regulatory regions of genes important for cancer transformation. Also genes mutated in CRC can have their epigenetic pattern altered and we suggest that changes in DNA methylation array can be important for CRC metastatic potential ‒ the main reason of CRC-associated mortality. These genes are: KRAS, genes of the Rho family of GTPases, MACC1, Met, MTA1 and RASSF1A. In addition, genes encoding miRNA important for epithelial mesenchymal transition and other metastasis-related effects, such as mir-9, miR-34 and miR-210 can be good candidates for associating their DNA methylation profiles with CRC metastasis. Analysis of DNA methylation profile in various stages of CRC along with other genetic/epigenetic changes specific for all main stages of CRC transformation could help in anti-metastatic therapy immediately after CRC diagnosis. However, targeting DNA methylation pattern in CRC therapy is a conception, which requires further work to precisely change DNA methylation array, without affecting genes, whose expression should not be changed.

Expression and variability of lipid metabolism genes in intracranial aneurysm.

The objective of this study was to investigate the association between mRNA expression and single nucleotide polymorphisms (SNPs) of the ATP-binding cassette transporter (ABCA1) gene, apolipoprotein A1 (APOA1) gene, low-density lipoprotein (LDLR) gene and RNA gene located in the CDKN2B-CDKN2A cluster (CDKN2B-AS1) involved in lipid metabolism and the occurrence of intracranial aneurysm (IA). Fifty three IA patients, and 27 controls (IA-free) were enrolled in this study and were genotyped for seven single nucleotide polymorphisms. Increased expression of the LDLR gene in IA patients was observed. The A/G genotype and the A allele of the c. -113G>A polymorphism of the APOA1 gene were associated with increased occurrence of IA (ORs 12.36 and 14.14, respectively), while the G/G genotype and G allele showed the opposite tendency (ORs 0.06 and 0.07, respectively). We also detected that the A/A-G/A combined genotype of the c. -113G>A - APOA1 and g.46859A>G - LDLR SNPs was associated with a decreased occurrence of IA. Moreover, the A/G-G/G combined genotype of the c.656G>A - ABCA1 and c. -113G>A - APOA1 was associated with a decreased occurrence of IA. The results of our study suggest the association between expression and variability of lipid metabolism genes and occurrence of IA.

Polymorphism of the LIG3 gene in keratoconus and Fuchs endothelial corneal dystrophy.

The product of the LIG3 gene encodes DNA ligase III, which is involved in the repair of oxidatively damaged DNA in the base excision repair pathway. We hypothesized that polymorphism in this gene may change susceptibility to oxidative stress and predispose individuals to the development of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Therefore, we investigated the association between genotypes and haplotypes of the g.29661G>A polymorphism (rs1003918) and the g.29059C>T polymorphism (rs1052536) of the LIG3 gene and the occurrence of KC and FECD in patients with FECD (258 individuals) or KC (283) and ethnically matched controls (300). The A/A genotype and the A allele of the g.29661G>A polymorphism were associated with increased occurrence of KC, while the G allele of this polymorphism was positively correlated with a decreased occurrence of this disease. The T/C genotype of the g.29059C>T polymorphism was associated with decreased FECD occurrence. In addition, the AT haplotype was associated with increased occurrence of KC and FECD, while the GT haplotype was associated with decreased occurrence of these diseases. The g.29661G>A and g.29059C>T polymorphisms may play a role in the KC and FECD pathogenesis and can be considered as markers in these diseases.

Mutagenesis of mitochondrial DNA in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is an age-related, slowly progressive disease, which may lead to loss of vision resulting from apoptosis of corneal endothelial (CE) cells, dysfunction of Descemet membrane (DM) and corneal edema. A growing body of evidence suggests that oxidative stress may play a major role in the pathogenesis of FECD and that mitochondria of CE cells are its main target. Mitochondrial DNA (mtDNA) is particularly prone to oxidative stress and changes in mtDNA were reported in FECD patients. In the present work we studied mtDNA damage and repair, mtDNA copy number, and the 4977bp common deletion in mtDNA in DM cells and peripheral blood lymphocytes (PBLs) isolated from FECD patients. PBLs from 35 FECD patients and 32 controls were challenged for 10min with hydrogen peroxide at 20µM and then left in a fresh medium for 3h, resulting in a decrease in mtDNA copy number in both groups. Damage to mtDNA was not fully repaired after 3h and the extent of remaining lesions was significantly higher in the patients than the controls. We observed a higher copy number and an increased extent of mtDNA damage as well as a higher ratio of the common 4977bp deletion in DM cells of FECD patients than the controls. Our results confirm that mutagenesis of mtDNA may be involved in FECD pathogenesis and disturbance in mtDNA sensitivity to damaging agent as well as changes in mtDNA damage repair along with alternations in mtDNA copy number may underline this involvement.

Mutations in the PAX9 gene in sporadic oligodontia.

OBJECTIVES: Oligodontia, a congenital lack of six or more teeth, is often associated with mutations in the PAX9 gene; therefore, we searched for mutations in this gene. DESIGN: In the present work, we sequenced fragments of the PAX9 gene in individuals with sporadic oligodontia. Next, we genotyped some mutations we found in patients with oligodontia and individuals without tooth agenesis. SETTING AND SAMPLE POPULATION: DNA sequencing was performed in the material isolated from peripheral blood lymphocytes of six unrelated patients with sporadic, non-syndromic oligodontia. These patients were selected based upon explorative cluster analysis. Genotyping was performed in 38 patients with oligodontia and 100 control individuals. MATERIAL AND METHODS: Direct sequencing and restriction fragment length polymorphism PCR were employed. RESULTS: We detected two homozygotic substitutions, IVS2-109G>C and IVS2-54A>G, in intron 2 in three patients. Another homozygotic substitution in intron 2, IVS2-41A>G, was revealed in two patients. Two patients had an IVS3+40G>A homozygotic change in intron 3 and 4 patients displayed a 717C>T transition in exon 4 (silent mutation). One patient had a heterozygotic 718G>C transversion, resulting in a missense Ala240Pro substitution. We detected also several other intronic substitutions. Further genotyping of the IVS2-54A>G, IVS2-109G>C, and IVS2-41A>G mutations suggested that they can display polymorphic changes. CONCLUSION: The IVS2-54A>G, IVS2-109G>C, and IVS2-41A>G mutations of the PAX9 gene may represent polymorphism associated with sporadic oligodontia.

Altered dopamine signalling in chronic epigastric pain syndrome.

Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The cause of this ailment is unclear. The aim of this study was the assessment of coexistence between symptoms of this syndrome and secretion level of dopamine (DA), as well as the efficacy of peripheral and central D2 receptors antagonist. Sixty depressive patients with CEPS occurring independently of the diet and with no Helicobacter pylori infection and 30 healthy subjects were enrolled in this study. Plasma DA and urinary homovanilic acid (HVA) concentration were measured by ELISA, and the mRNA expression of dopa decarboxylase (DDC) in gastric mucosa was evaluated by RT-PCR in 30 patients with CEPS and 30 controls. Severity of epigastric pain before and after 12 weeks 2 x 50 mg itopride or sulpiride treatment was evaluated using the modified 10-point Visual Analogue Scale. Higher average levels of plasma DA and urinary HVA levels in CEPS patients than controls 129.5 ± 22.0 versus 109.1 ± 18.4 pg/ml (p < 0.001) and 6.82 ± 1.55 versus 5.39 ± 1.04 mg/24 h, respectively were obtained. Moreover, the expression of DDC in gastric mucosa of CEPS patients was higher than in healthy subjects (p < 0.01). Sulpiride subsided epigastric pain in 73.3%, but itopride reduced it only in 6.6% of CEPS patients. We concluded that altered dopamine signalling may affect locally-and-centrally mediated chronic epigastric pain.

Effect of gliclazide on DNA damage in human peripheral blood lymphocytes and insulinoma mouse cells.

Type 2 diabetes mellitus is associated with increased oxidative stress. Free radicals produced during this stress may damage various cellular components. Gliclazide, a second-generation sulfonylurea, is an oral hypoglycemic drug that possesses antioxidant properties. Therefore, gliclazide may diminish the harmful consequences of oxidative stress in diabetic patients. The aim of our study was to evaluate the action of gliclazide on DNA damage and repair in normal human peripheral blood lymphocytes and insulinoma mouse cells (beta-TC-6). DNA damage and repair were induced by hydrogen peroxide, gamma and ultraviolet radiation and MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) in the presence or absence of gliclazide and were analysed by the alkaline comet assay. DNA double-strand breaks were assayed by pulsed-field gel electrophoresis. Gliclazide protected DNA of both kinds of cells from DNA damage induced by chemicals and radiations. These results suggest that gliclazide may diminish the risk of free radical-related diseases associated with type 2 diabetes mellitus and possibly cancer.

The Trp64Arg beta3-adrenergic receptor amino-acid variant is not associated with overweight and type 2 diabetes mellitus in Polish population.

The Trp64Arg amino-acid variant of the beta3 adrenoreceptor gene may be associated with a genetic predisposition to human obesity and related disorders, including type 2 diabetes mellitus. This relationship has been reported in various ethnic groups, however it was not extensively studied in Polish population. Therefore, the aim of the study was to investigate the association of Trp64Arg polymorphism of the beta3 adrenergic receptor gene with overweight and type 2 diabetes mellitus in polish subjects. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism (PCR-RFLP). The study population consisted of 358 subjects, among whom 200 were diagnosed as overweight (BMI > 27 kg/m (2)). Among overweight subjects 111 presented with type 2 diabetes mellitus and 89 with normal glucose metabolism. All study participants were unrelated Caucasians and inhabited the city of Lodz, Poland. The frequency of the Arg allele did not differ significantly between overweight and normal weight patients (13 % vs. 11 %, OR 1.17, CI 0.74 - 1.85). The same applied to overweight diabetic patients vs. overweight patients without diabetes mellitus (13 % vs. 13 %, OR 0.97, CI 0.54 - 1.76). The obtained results suggest no association between Trp64Arg polymorphism of the beta3-AR gene and the incidence of overweight and type 2 diabetes mellitus in Polish population.

Polymorphism of DNA mismatch repair genes in endometrial cancer.

UNLABELLED: Endometrial cancer (EC) is the second most common malignancy associated with hereditary non-polyposis colorectal cancer (HNPCC) family. The development of HNPCC is associated with defects in DNA mismatch repair (MMR) pathway resulting in microsatellite instability (MSI). MSI is present in a greater number of EC than can be accounted for by inherited MMR mutations, therefore alternative mechanisms may underline defective MMR in EC, including polymorphic variation. AIM: We checked the association between EC occurrence and two polymorphisms of MMR genes: a 1032G>A (rs4987188) transition in the hMSH2 gene resulting in a Gly22Asp substitution and a -93G>A (rs1800734) transition in the promoter of the hMLH1 gene. MATERIAL AND METHODS: These polymorphisms were genotyped in DNA from peripheral blood lymphocytes of 100 EC patients and 100 age-matched women by restriction fragment length polymorphism PCR. RESULTS: A positive association (OR 4.18; 95% CI 2.23-7.84) was found for the G/A genotype of the -93G>A polymorphism of the hMLH1 gene and EC occurrence. On the ot-her hand, the A allele of this polymorphism was associated with decreased EC occurrence. The Gly/Gly genotype slightly increased the effect of the -93G>A-G/A genotype (OR 4.52; CI 2.41-8.49). Our results suggest that the -93G>A polymorphism of the hMLH1 gene singly and in combination with the Gly322Asp polymorphism of the hMSH2 gene may increase the risk of EC.

ABL-fusion oncoproteins activate multi-pathway of DNA repair: role in drug resistance?

Chromosomal translocations of tyrosine kinase c-ABL gene from chromosome 9 may generate oncogenic kinases exhibiting constitutive tyrosine kinase activity. Recently, we have shown that ABL-fusion oncogenic tyrosine kinases, BCR/ABL and TEL/ABL, specific to hematopoietic malignances, induced resistance to DNA-damaging agents. To elucidate the role of DNA repair in this phenomenon we examined the capacity of murine BaF3 lymphoid cells and their TEL/ABL-transformed counterparts to repair DNA lesions caused by gamma- and UV-radiations and the anti-cancer drug, idarubicin. TEL/ABL-transformed cells displayed resistance to these DNA damaging agents as evaluated by MTT assay and the survival advantage was associated with an accelerated kinetics of DNA repair as measured by the alkaline comet assay. Deoxyribonucleosides (dNTPs) supplementation of the repair medium further stimulated DNA repair and the effect was specific to the DNA damage agent used in the experiment but only the transformed cells displayed this feature. A variety of damages induced imply the multi-pathway of DNA repair involved. We also examined the capability of BCR/ABL-fusion to modulate the repair of oxidative lesions, considered as a major side effect of various anti-cancer drugs including idarubicin and radiation. Employing the free radical scavenger alpha-phenyl-N-tert-butyl nitrone (PBN, a spin trap) and DNA repair enzymes: endonuclease III (EndoIII) that nicks DNA at sites of oxidized bases, we found that BCR/ABL-transformed cells repaired oxidative DNA lesions more effectively than control cells. Our results suggest, that oncogenic ABL-dependent stimulation of DNA repair may contribute to the cell resistance to genotoxic treatment.

Antigen levels of the urokinase-type plasminogen activator and its gene polymorphisms in colorectal cancer.

We analysed the distribution of genotypes of two polymorphisms in the urokinase-type plasminogen activator (uPA) gene: C-->T substitution in exon 6 and T-->C substitution in intron 7 in 52 subjects with colorectal cancer. Genotypes were determined in tumour tissue and distant mucosa samples by allele-specific polymerase chain reaction. The antigen levels of uPA in cancer tissue were higher than in distant mucosa as measured by enzyme-linked immunosorbent assay. The level of uPA antigens in cancer samples with the C/C genotype of C-->T polymorphism in exon 6 was higher than in samples with C/T and T/T genotypes. No differences in the level of uPA antigens between the alleles of the intron 7 T-->C polymorphism were found. As uPA can be involved in cancer invasion and metastasis, C/C genotype in exon 6 of uPA gene can be further considered as being related to colorectal cancer progression.

Plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G promoter polymorphism is not associated with breast cancer.

The antigen content of plasminogen activator inhibitor-1 (PAI-1) in primary breast cancer tissue extracts may be of strong prognostic value: high levels of PAI-1 in tumors predict poor prognosis for patients. The gene encoding PAI-1 is highly polymorphic and an insertion (5G)/deletion (4G) polymorphism in the PAI-1 gene promoter (the 4G/5G polymorphism), may have functional significance in PAI-1 expression. In the present work the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism in subjects with breast cancer were investigated. Tumor tissues were obtained from 100 postmenopausal women with node-negative and node-positive ductal breast carcinoma with uniform tumor size. Blood samples from age matched healthy women served as control. The 4G/5G polymorphism was determined by PCR amplification using the allele specific primers. The distribution of the genotypes of the 4G/5G polymorphism in both control and patients did not differ significantly (P > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no differences in the genotype distributions and allele frequencies between node-positive and node-negative patients. The 4G/5G polymorphism may not be linked with elevated level of PAI-1 observed in breast cancer and therefore may not be associated with appearance and/or progression of breast cancer.

Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate.

Genotoxicity of anticancer drugs is of a special interest due to the risk of inducing secondary malignancies. Vitamin C (ascorbic acid) is a recognized antioxidant and, since human diet can be easily supplemented with vitamin C, it seems reasonable to check whether it can protect against DNA-damaging effects of antitumor drugs. In the present work the ability of vitamin C to modulate cytotoxic and genotoxic effects of a cisplatin analog, conjugate (NH3)2Pt(SeO3), in terms of cell viability, DNA damage and repair in human lymphocytes was examined using the trypan blue exclusion test and the alkaline comet assay, respectively. The conjugate evoked a concentration-dependent decrease in the cell viability, reaching nearly 50% at 250 microM. (NH3)2Pt(SeO3) at 1, 10 and 30 microM caused DNA strand breaks, measured as the increase in the comet tail moment of the lymphocytes. The treated cells were able to recover within a 30-min incubation in a drug-free medium at 37 degrees C. Vitamin C at 10 and 50 microM diminished the extent of DNA damage evoked by (NH3)2Pt(SeO3) but had no effect on the kinetics of DNA repair. The vitamin did not directly inactivate the conjugate. Lymphocytes treated with endonuclease III, which recognises oxidised pyrimidines, displayed a greater tail moment than those untreated with the enzyme, suggesting that the damages induced by the drug have, at least in part, an oxidative origin. Vitamin C can be considered a potential protective agent against side effects of antitumor drugs, but further research with both normal and cancer cells are needed to clarify this point.

The changes of osmotic fragility of pig erythrocytes induced by organophosphorus insecticides.

Organophosphorus insecticides: methylbromphenvinphos, dichlorvos, malathion and methylparathion exert antilytic effects on pig erythrocytes by preventing osmotic disruption of membranes in hypotonic saline media. The order of effectiveness is the following: methylbromphenvinphos, methylparathion, malathion, dichlorvos.

A comparison of the in vitro genotoxicity of tri- and hexavalent chromium.

Chromium can be found in the environment in two main valence states: hexavalent (Cr(VI)) and trivalent (Cr(III)). Cr(VI) salts are well known human carcinogens, but the results from in vitro studies are often conflicting. Cr(VI) primarily enters the cells and undergoes metabolic reduction; however, the ultimate product of this reduction, Cr(III) predominates within the cell. In the present work, we compared the effects of tri- and hexavalent chromium on the DNA damage and repair in human lymphocytes using the alkaline single cell gel electrophoresis (comet assay). Potassium dichromate induced DNA damage in the lymphocytes, measured as the increase in comet tail moment. The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Cr(III) caused greater DNA migration than Cr(VI). The lymphocytes did not show measurable DNA repair. Vitamin C at 50 microM reduced the extent of DNA migration. This was either due to a decrease in DNA strand breaks and/or alkali labile sites induced by Cr(VI) or to the formation of DNA crosslinks by Cr(VI) in the presence of vitamin C. Vitamin C, however, did not modify the effects of Cr(III). Catalase, an enzyme inactivating hydrogen peroxide, decreased the extent of DNA damage induced by Cr(VI) but not the one induced by Cr(III). Lymphocytes exposed to Cr(VI) and treated with endonuclease III, which recognizes oxidized pyrimidines, displayed greater extent of DNA damage than those not treated with the enzyme. Such an effect was not observed when Cr(III) was tested. The results obtained suggest that reactive oxygen species and hydrogen peroxide may be involved in the formation of DNA lesions by hexavalent chromium. The comet assay did not indicate the involvement of oxidative mechanisms in the DNA-damaging activity of trivalent chromium and we speculate that its binding to cellular ligands may play a role in its genotoxicity.

In vitro studies on the genotoxicity of the organophosphorus insecticide malathion and its two analogues.

Malathion [S-(1,2-dicarboethoxyethyl)O,O-dimethyl phosphorodithioate] is a commonly used organophosphorus insecticide reported to be genotoxic both in vivo and in vitro, but the reports are conflicting. In order to elucidate the genotoxic potency of the main compounds present in commercial preparations of malathion, the DNA-damaging effect of this insecticide, its major metabolite malaoxon [S-(1,2-dicarboethoxyethyl)O,O-dimethyl phosphorothiolate] and its isomer isomalathion [S-(1,2-dicarboethoxyethyl)O,S-dimethyl phosphorodithioate], all at purity of at least 99.8%, was investigated by use of the alkaline single cell gel electrophoresis (comet assay). Freshly isolated human peripheral blood lymphocytes were incubated with 25, 75 and 200 microM of the chemicals for 1 h at 37 degrees C. The concentrations used are comparable to those found in blood following various non-lethal human exposures to pesticides. Malathion did not cause any significant changes in the comet length of the lymphocytes, throughout the range of concentrations tested. Malaoxon and isomalathion introduced damage to DNA in a dose-dependent manner. The effect induced by malaoxon was more pronounced than that caused by isomalathion. Treated cells were able to recover within a 60-min incubation in insecticide-free medium at 37 degrees C except the lymphocytes exposed to malaoxon at 200 microM, which did not show measurable DNA repair. The latter result suggests a considerable cytotoxic effect (cell death) of malaoxon at the highest concentration used. The reported genotoxicity of malathion might, therefore, be a consequence of its metabolic biotransformation to malaoxon or the presence of malaoxon and/or isomalathion as well as other unspecified impurities in commercial formulations of malathion. In this regard, the results of our study clearly indicate that malathion used as commercial product, i.e., containing malaoxon and isomalathion, can be considered as a genotoxic substance in vitro. This means that it may also produce DNA disturbances in vivo, such as DNA breakage at sites of oncogenes or tumor suppressor genes, thus playing a role in the induction of malignancies in individuals exposed to this agent. Therefore, malathion can be regarded as a potential mutagen/carcinogen and requires further investigation.

Curcumin damages DNA in human gastric mucosa cells and lymphocytes.

The naturally occurring pigment curcumin, a major component of the spice turmeric, is reported to be a potent inhibitor of the initiation and promotion of many cancers. Due to its presence in the diet, one of its primary targets is the human gastric mucosa (GM) cells. Using the sensitive single cell electrophoresis method (comet assay), we found that curcumin at of 15, 25, and 50 microM caused DNA damage in GM cells and human peripheral blood lymphocytes. There was no difference between the extent of the damage in both types of cells. Damaged cells were able to recover within a period of 120 minutes. Our results indicate that curcumin may play a dual role in carcinogenesis.

In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells.

The influence of ethanol and acetaldehyde on DNA in human lymphocytes, gastric mucosa (GM) and colonic mucosa (CM) was investigated by using the comet assay. All kinds of cells were exposed to ethanol and acetaldehyde in two regimens: the cells were incubated with either chemical and analysed or they were exposed first to ethanol, washed and then exposed to acetaldehyde and analysed. Lymphocytes were exposed to ethanol at final concentrations of 30 mM and acetaldehyde at 3 mM. GM cells were incubated with ethanol at 1 M and acetaldehyde at 100 mM. CM cells were exposed to ethanol at 10 mM and acetaldehyde at 100 mM. In combined exposure, the cells were subsequently exposed to ethanol and acetaldehyde at all combination of the concentrations of the agents. Ethanol caused DNA strand breaks, which were repaired during 4 hr, except when this agent was applied in GM cells at a concentration of 1 M. A dose-dependent decrease in the tail moment of all types of acetaldehyde-treated cells was observed. Similar results were obtained when a recognized DNA crosslinking agent, formaldehyde, was used. These results suggest that acetaldehyde may form crosslinks with DNA. These crosslinks were poorly repaired. CM cells showed the highest sensitivity of all cell types to ethanol than lymphocytes and GM cells. There were no differences in the sensitivity to acetaldehyde of all the cell types. Our results clearly indicate that ethanol and acetaldehyde can contribute to cancers of the digestive tract.

An association of polymorphism of DNA repair genes XRCC1 and XRCC3 with colorectal cancer.

Variability in DNA repair genes may contribute to human cancer risk. We performed a case-control study (51 cases and 100 controls) to test the association between two polymorphisms: Arg399Gln in the XRCC1 gene and Thr241Met in the XRCC3 gene and colorectal cancer risk. Genotypes were determined in tumour tissue and distant mucosa samples by PCR RFLP with the NciI restriction enzyme for XRCC1 and NcoI for XRCC3. Cancer occurrence was strongly associated with the XRCC3 Met/Met polymorphic variant (OR = 9.45; (95% CI 8.77-11.65)), whereas Thr/Thr and Thr/Met variants were associated with significant reduction in colorectal cancer risk (OR = 0.16; 95% CI 0-0.26 and OR = 0.26; 95% CI 0.25-0.27, respectively). Weak association was found between the XRCC1 Arg/Arg and Gln/Gln variants and the risk of colorectal cancer (OR = 1.28; 95% CI 1.00-1.84 and OR = 1.13; 95% CI 0.85-2.34, respectively). Gene-gene interaction between the XRCC1 Arg/Arg and XRCC3 Met/Met homozygous variants slightly increased the risk (OR = 10.50; 95% CI 5.67-14.79). Both polymorphisms were not associated with colorectal cancer progression.

An association between the Trp64Arg polymorphism in the beta3-adrenergic receptor gene and endometrial cancer and obesity.

Beta3-adrenergic receptor (beta3AR) stimulates lipolysis in human fat cells, so its gene can constitute a candidate to explain a part of genetic predisposition to human obesity and related disorders. The Trp64Arg polymorphism in the beta3AR gene has been reported to be associated with insulin resistance, obesity and type 2 diabetes; little is known about its possible association with cancer. To check this association we determined the distribution of its genotypes and frequency of alleles in endometrial cancer patients with or without overweight/obesity as compared to appropriate controls. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism in DNA of peripheral blood leukocytes. The study population consisted of 169 subjects, among them were 79 endometrial cancer patients and 90 controls without cancer. There were 34 obese (BMI > or = 30 kg/m2) and 22 overweight (30 BMI > or = BMI > or = 27 kg/m2) individuals among endometrial cancer patients. There was a significant (p < 0.001) difference in genotype distribution and allele frequency between endometrial cancer patients and controls without cancer. The odds ratios for the Trp/Arg and Arg/Arg genotypes as well as for the Arg allele were considerably higher than 1. Analysis of the polymorphism in the cancer group patients due to BMI revealed that the distribution of genotypes and the frequency of alleles in obese/overweight patients differed significantly from those in patients with normal weight with an odds ratio for the Trp/Arg genotype and the Arg allele of about 4. The prevalence of the Arg allele of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene may contribute to the susceptibility to endometrial cancer among obese/overweight individuals.