Polymorphisms in nucleotide excision repair genes and susceptibility to colorectal cancer in the Polish population.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (XPA-XPG) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with XPC polymorphism rs2228000_CT genotype (OR 0.59; p < 0.0001) and the rs2228000_TT genotype (OR 0.29; p < 0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the XPD SNP, rs1799793_AG genotype (OR 1.44, p = 0.018) and rs1799793_AA genotype (OR 3.31, p < 0.0001) compared to the reference genotype. Haplotype analysis within XPC, XPD and XPG revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs: XPC rs2228000, XPD rs1799793 and XPD rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in XPD (rs1799793) and XPC (rs2228000) revealed differences in the prevalence of these variants in patients under and over 50 years of age. Our results confirmed that polymorphisms in XPC and XPD may be associated with the risk of colorectal cancer.

Is plasma soluble CD36 associated with cardiovascular risk factors in early onset coronary artery disease patients?

BACKGROUND AND PURPOSE: This is the first study to investigate the relationship between plasma concentration of soluble CD36 (sCD36) and CD36 gene polymorphisms as well as clinical and echocardiographic parameters in patients with early onset coronary artery disease (CAD). METHODS: sCD36 concentrations were measured by the ELISA kits. CD36 sequence alterations detected by the DHPLC technique comprised single nucleotide substitutions: rs3173798, rs3211892, rs5956 and rs141680676. RESULTS: There were significant negative correlations between sCD36 and red blood cell count, hemoglobin, hematocrit and glucose concentration, ApoB/ApoA1 ratio, patients' weight and waist circumference, BMI, WHR, systolic blood pressure, MAP values, left ventricular end-diastolic diameter and volume, left atrium diameter, right ventricular end-diastolic diameter. There were significant positive correlations between sCD36 and patients' age, mean corpuscular volume of erythrocytes, HDL-cholesterol, ApoA1 concentrations. Significantly higher CD36 plasma levels were found in female subgroup. There was no association between CD36 genotypes and sCD36 concentrations. Multiple linear regression analysis revealed that significant independent predictors of higher plasma sCD36 level were female gender, older age, lower serum glucose and lower RBC. CONCLUSION: The presented data suggest possible protective effects of higher sCD36 concentration in relation to metabolic syndrome components in CAD patients. Higher sCD36 concentration is also associated with lower risk of left ventricular hypertrophy, but on the other hand is a potential risk factor of impaired left ventricle diastolic function.

Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families.

BACKGROUND: Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. METHODS: We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria). RESULTS: Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery. We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) early-onset patients from LS families died from OC within 2 years of diagnosis. We confirmed a significantly increased risk of EC (OR = 26, 95% CI 11,36-58,8; p < 0,001). The cumulative risk for EC in Polish LS families was calculated to be 67%. CONCLUSIONS: Due to the increased risk of OC and absence of any benefit from gynecological screening reported in the literature it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound supported by CA125 or HE4 marker testing should be performed after prophylactic surgery in these women. Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound supported by routine aspiration sampling of the endometrium for women from either LS or HNPCC families. An alternative option, which could be taken into consideration for women preferring surgical prevention, is risk reducing total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete.

Combined analysis of three Lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers.

Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.

Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review.

Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.

Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in Lynch syndrome.

OBJECTIVE: Recently, six colorectal cancer (CRC) susceptibility loci have been identified, and two single-nucleotide polymorphisms (SNPs)--rs16892766 (8q23.3) and rs3802842 (11q23.1)--from two of these regions have been found to be significantly associated with an increased CRC risk in patients with Lynch syndrome. The objective of this study was to genotype nine SNPs within these six loci to confirm previous findings and investigate whether they act as modifiers of disease risk in patients with Lynch syndrome. DESIGN: The patient cohort consisted of 684 mutation-positive patients with Lynch syndrome from 298 Australian and Polish families. Nine SNPs were genotyped: rs16892766 (8q23.3), rs7014346 and rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs10318 and rs4779584 (15q13.3), and rs4939827 and rs4464148 (18q21.1). The data were analysed to investigate possible associations between the presence of variant alleles and the risk of developing disease. RESULTS: An association between SNP rs3802842 on chromosome 11q23.1 and rs16892766 on chromosome 8q23.3 and the risk of developing CRC and age of diagnosis was found in MLH1 mutation carriers. Female MLH1 mutation carriers harbouring the homozygous variant genotype for SNP rs3802842 have the highest risk of developing CRC. When the number of risk alleles for the two SNPs combined was analysed, a difference of 24 years was detected between individuals carrying three risk alleles and those carrying no risk alleles. CONCLUSION: The authors were able to replicate the association between the CRC susceptibility loci on chromosomes 8q23.3 and 11q23 and the risk of developing CRC in patients with Lynch syndrome, but the association could only be detected in MLH1 mutation carriers in this study.

Polymorphism of the CD36 Gene and Cardiovascular Risk Factors in Patients with Coronary Artery Disease Manifested at a Young Age.

This study investigates potential associations between CD36 gene variants and the presence of risk factors in Caucasians with coronary artery disease (CAD) manifested at a young age. The study group consisted of 90 patients; the men were ≤ 50 years old and the women were ≤ 55 years old. Amplicons of exons 4 and 5 including fragments of introns were analyzed by DHPLC. Two polymorphisms were found: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892). The C allele of the IVS3-6 T/C polymorphism was associated with higher prevalence of obesity and diabetes, higher hsCRP, lower Lp(a) serum concentrations, and younger age at myocardial infarction. The A allele of the IVS4-10 G/A polymorphism was associated with older age of myocardial infarction and higher white blood cell count. The functional role of CD36 polymorphisms in CAD development needs further research.

Polymorphism of CD36 gene, carbohydrate metabolism and plasma CD36 concentration in obese children. A preliminary study.

INTRODUCTION: CD36 may play an important role in removal of oxidized LDLs from plasma, protein glycation, the pathogenesis of insulin resistance, type 2 diabetes, and diabetic micro- and macroangiopathy. Some reports have pointed to decreased expression of macrophages in association with mutations of the CD36 gene in hyperglycemic and obese subjects. The aim of the study was to search for an association between CD36 gene polymorphism and carbohydrate metabolism disturbances or variability of plasma soluble CD36 concentrations in obese children. MATERIAL/METHODS: The study included 60 children aged 10 to 15 years: 30 with (study group) and 30 without (control group) obesity. Each patient's glycated hemoglobin, weight, height, waist and hip circumference, and systolic and diastolic blood pressure were measured, BMI, WHR and MAP were calculated, and oral glucose tolerance test was performed with glucose and insulin concentration measurements. Amplicons of exons 4-6 of CD36 were studied using DHPLC technique. The PCR products with alterations were bidirectionally sequenced. Plasma concentrations of human antigen CD36 was measured using a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: We found two intronic alterations: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892), one nonsynonymous substitution: G367A (Glu123Lys, rs183461468) in exon 5 and two synonymous transitions in exon 6: G573A (Pro191Pro, rs5956) and A591T (Thr197Thr, rs141680676). There were no significant differences in any biochemical or morphometric parameters between genotype groups. DISCUSSION: The polymorphisms of the studied fragment of CD36 are not associated with carbohydrate metabolism disturbances or the variability of plasma soluble CD36 concentrations in obese children, but further research is necessary to assess their functional implications.

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.

Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.

CHEK2 mutations and HNPCC-related colorectal cancer.

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR = 2.1; p = 0.0004), but not for MMR-positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.

Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility.

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.

Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.

IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer.

Patients diagnosed with HNPCC harbouring a confirmed germline mutation in DNA mismatch repair (MMR) genes have an 80% lifetime risk of developing an epithelial malignancy. There is, however, considerable variation in the age of disease onset in these patients. Insulin-like growth factor-I (IGFI) has been implicated in colorectal cancer (CRC), and elevated plasma IGFI levels are associated with both sporadic and hereditary CRC risk. In this study, we further investigate the cytosine-adenine (CA) dinucleotide repeat polymorphism located near the promoter region of IGF1 and its relation to early onset CRC risk in 443 Australian and Polish MMR gene mutation carriers using DNA sequencing, Kaplan-Meier survival curves and Cox proportional hazard regression analysis. A significantly smaller number of IGF1 CA repeats was observed in the Polish patient population, which was associated with an earlier age of disease onset compared to the Australian patients. The threshold for the observed modifying effect was again shown to be in patients with 17 or less CA repeats compared to those with 18 or more. Furthermore, when MMR mutation group (i.e., MLH1 or MSH2), gender and family clustering were included in the final Cox model we observed a more robust trend for the role of the IGF1 CA repeat in predicting age of disease onset in HNPCC patients. In addition, this effect was shown to be equal in both MLH1 and MSH2 mutation carrier groups and not restricted to a particular MMR subgroup (p = 0.001). We conclude that the IGF1 CA repeat is an important modifier of disease onset in HNPCC and the first polymorphism to yield consistent results across different populations.

Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer.

Polymorphisms in the 2 cell-cycle control genes Aurora A and Cyclin D1 have previously been associated with changes in the age of onset of colorectal cancer in persons harboring germline mutations in DNA mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). In this report, we have genotyped 312 individuals, who all harbored confirmed causative mutations in either hMSH2 or hMLH1, for 2 polymorphisms, one in Aurora A (T91A) and the other in Cyclin D1 (G870A). The results reveal that the previous association with the Aurora A polymorphism could not be confirmed in our larger group of HNPCC patients. The Cyclin D1 polymorphism, however, was associated with a significant difference in the age of disease onset on patients harboring hMSH2 mutations, which was not observed in hMLH1 mutation carriers. A combined analysis of the Aurora A and Cyclin D1 polymorphisms did not reveal any obvious association. In conclusion, it appears that the polymorphic variant of Aurora A does not appear to be associated with variation in colorectal cancer risk in HNPCC, whereas there is a more complex relationship between the Cyclin D1 polymorphism and disease risk in HNPCC.

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

BACKGROUND: Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers. METHODS: In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFalpha) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls). RESULTS: Of the six genes only one polymorphism in TNFalpha(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFalpha -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFalpha -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs). CONCLUSION: The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.

Frequency of mutations related to hereditary haemochromatosis in northwestern Poland.

Hereditary haemochromatosis has been linked with C282Y and H63D mutations of the HFE gene. In Europe, frequencies of these mutations are the highest in Northern European countries and gradually decrease southwards. We analysed the prevalence of HFE mutations in 1517 DNA samples, including 1000 samples from the general population (subjects registered at general practitioner practices) in northwestern Poland, and 517 samples of cord blood from the same region. We identified 2 (0.13%) homozygotes and 117 (7.8%) heterozygotes for the C282Y mutation. As regards the H63D mutation (1505 DNA samples analysed), 38 (2.5%) samples were homozygotes and 380 (25%) were heterozygotes. Twenty-one (1.4%) compound heterozygotes were found. These results correspond well with data from other Central European countries and seem to confirm the hypothesis of North-South spread of the C282Y mutation.

Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Germline mutations in cell cycle checkpoint kinase 2 (CHEK2) have been associated with a range of cancer types, in particular of the breast and prostate. Protein-truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate than the missense I157T variant. In order to estimate the risks of colorectal cancer associated with truncating and missense CHEK2 mutations, we genotyped 1085 unselected colorectal cancer cases and 5496 controls for four CHEK2 founder mutations present in Poland. We observed an increased risk of colorectal cancer in association with the missense I157T mutation (odds ratios (OR) = 1.5; 95% CI 1.2-2.0; P = 0.002) but not with truncating mutations (OR = 1.0; 95% CI 0.5-1.8; P = 0.9); however the difference in the two OR was not statistically significant (P = 0.2). We conclude that the I157T mutation increases the risk of colorectal cancer in the population, but that truncating mutations may confer a lower risk or no increase in risk. It is important that other studies of CHEK2 mutation carriers be conducted to confirm this hypothesis.

CARD15 variants in patients with sporadic Parkinson's disease.

Recent reports have proven the importance of genetic factors and inflammation in the pathogenesis of sporadic Parkinson's disease (PD). In the current study, the frequency of CARD15/NOD2 gene variants (R702W, G908R, L1007fs), previously associated with Crohn's disease--a common inflammatory bowel disease, have been examined in a group of 308 sporadic PD patients and 220 healthy controls. Significantly higher frequency of total CARD15 variant alleles in PD patients (13.0%) compared to the controls (8.0%, p<0.02) was observed. 24.0% of PD patients carried at least one CARD15 variant allele compared to 15.5% of healthy controls (p<0.02, OR=1.73). The results of the study suggest, that the polymorphism in CARD15/NOD2 gene may be a risk factor for sporadic PD development, and support the concept of inflammatory pathogenesis of PD.

Nationwide study of clinical and molecular features of hereditary non-polyposis colorectal cancer (HNPCC) in Latvia.

BACKGROUND: The mutational spectrum of mismatch repair (MMR) genes in the Baltic States has been reported to be quite similar to that in Poland; however during a country-wide study considerable differences in the population of Latvia were discovered. This study was undertaken to investigate the clinical and molecular features of HNPCC in Latvia. MATERIALS AND METHODS: Family cancer histories were collected, from January 2000 until October 2003, for 702 consecutive hospital based colorectal cancer (CRC) cases. In families suspected of having a history consistent with hereditary non-polyposis colorectal cancer (HNPCC), DNA testing for MLH1, MSH2 and MSH6 genes was performed. Immunohistochemical examination of the normal and the cancer tissue from large bowel tumors was undertaken for MSH2 and MSH6 protein expression in 182 out of 702 (26%) of the cases. RESULTS: Among the 702 CRC patients only 1 (0.14%) fulfilled the Amsterdam criteria. Thirteen (1.9%) cases matched the criteria for suspected HNPCC and 10 (1.4%) cases matched the late onset HNPCC criteria. Altogether in 7 out of 702 (1%) cases MMR gene mutations were detected: 2 in MLH1, 3 in MSH2 and 2 in MSH6 gene. Only one out of the seven mutations was registered in the Human Genome Mutation Database and the ICG (International Collaborational Group)-HNPCC mutation data base. Negative MSH2 and MSH6 protein expression was detected in 4 (2.2%) and 18 out of 182 (9.9%) cases respectively. CONCLUSION: The role of the classical Amsterdam criteria in diagnosing HNPCC in CRC patients from Latvia is very limited and diagnostic criteria for suspected HNPCC are the most effective. The frequency of constitutional mutations within the MMR genes is 1% of all newly diagnosed CRC cases and the spectrum of mutations is potentially characteristic.

CDKN2A common variants and their association with melanoma risk: a population-based study.

The population frequencies of the CDKN2A variants remain undetermined. In Poland there are three common variants of CDKN2A: an alanine to threonine substitution (A148T), Nt500c>g and Nt540c>t, which have been detected in other populations. To establish if they are associated with an increased malignant melanoma (MM) risk we did an association study based on genotyping 471 patients with MM and 1,210 random control subjects from the same Polish population. We found a significantly increased frequency of the A148T variant among patients with MM (7.0%) in comparison with the general population (2.9%). The incidence of the A148T variant remained greater in both unselected and familial melanoma subgroups. A statistically significant positive association was seen for unselected MM (odds ratio, 2.529; P = 0.0003), especially in patients diagnosed under 50 years of age (odds ratio, 3.4; P = 0.0002). The A148T carrier population (heterozygous G/A alleles) was more likely to have a relative with malignancy compared with the noncarrier population (57% versus 36%, respectively; P = 0.03). Further examination of the CDKN2A promoter sequence done in 20 melanoma patients with the A148T change (heterozygous G/A alleles) and 20 patients with MM without this alteration identified it was in linkage disequilibrium with a polymorphism in the promoter region at position P-493. We found no statistically significant overrepresentation of the Nt500c>g and the Nt540c>t polymorphisms in the Polish melanoma population. In conclusion, the A148T variant of the CDKN2A gene seems to be associated with an increased risk of development of MM. Additional studies are required to confirm whether this particular change is associated with increased risk of other nonmelanoma malignancies.