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Mutations of genes associated with the mismatch repair mechanism and mutations of the APC gene are the most frequent causes of hereditary colorectal cancer. An iPLEX test combined with TaqMan genotyping assays was therefore developed to identify common recurrent mutations of those genes in the Polish population. We analyzed 349 DNA samples from 95 positive controls previously identified by sequencing and 254 unexamined individuals. The iPLEX test included two plexes, which comprised seven mutations of the APC gene and 29 mutations of three of the mismatch repair genes. TaqMan assays were designed for nine mutations not covered by the iPLEX assays: one mutation in the APC gene and eight mutations in the mismatch repair genes. Results were then verified independently by sequencing. Our combination method allowed detection of all recurrent mutations occurring in group of patients, followed by full analysis by DNA sequencing. With the exception of one false positive in the iPLEX test in the positive control group that could be assigned to contamination from neighboring wells rather than a detection error, given sufficient DNA concentration and quality, the designed iPLEX/TaqMan test had an accuracy of 100% for the designed assays. These results suggest that the combined iPLEX/TaqMan test is an outstanding tool for identification of recurrent mutations among hereditary colorectal cancer patients.

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.

A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.

Backgroud 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, TNFα) 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 TNFα(-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 TNFα -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 TNFα -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.

DNA testing is recommended in families fulfilling at least "suspected HNPCC" criteria. After exclusion of FAP (characteristic FAP features include polyposis, congenital hypertrophy of the retinal pigment epithelium, cysts and osteomata of bones of the maxilla and mandible, desmoid tumours), immunohistochemical analyses (IHC) of MLH1, MSH2 and MSH6 expression in malignant tissues should be performed (absence of the protein may indicate the mutated gene). The results of several studies performed in our centre characterised the frequencies and spectrum of MSH2 and MLH1 mutations in Poland [1]. Similarly to other populations, the most frequent causes of HNPCC in Poland are MLH1 and MSH2 mutations, constituting 90% of all mutations associated with this syndrome. MLPA detects 10% of these mutations. In over 60% of all HNPCC families recurrent mutations can be found. Thus after IHC, MLPA for MSH2 and MLH1 should be performed. Next, with MLPA negative, DNA tests searching for recurrent mutations, characteristic for the Polish population, should be applied. The last step should include DHPLC [2] and sequencing of the cases indicated by DHPLC results.

With the instigation of population screening strategies to reduce the burden of colorectal cancer, a cost effective approach remains an elusive goal. Genetic markers associated with colorectal cancer have the potential to be used for the early identification of patient groups at elevated risk of disease. The choice of genetic markers that can be used for screening purposes is population specific. In this report we have genotyped 3059 individuals for 13 markers that have been associated with colorectal cancer risk. The participants underwent colonoscopy and controls with clear colonoscopy (1838) were compared to cases with advanced colorectal neoplasia (213). Logistic regression analysis, adjusted for sex and age at colonoscopy, showed that only one of the markers (rs4779584) was significantly associated with the risk of advanced colorectal neoplasia (OR = 1.93; 95% CI = 1.22 – 2.99; p-value = 0.004; sensitivity = 20%). A combination of 7 markers (rs4779584, rs2578187, rs3802842, rs6983267, NOD2 5020insC, rs4464148 and rs4939827) showed an optimal trade-off minimizing the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it (e.g. for at least 4 cumulated risk markers, OR = 4.23; 95% CI = 1.5 – 10.4; p-value = 0.0036; sensitivity = 4.7%). For this combination of 7 markers the linear cumulative risk model was statistically significant (p=7.0·10-5) after adjustment for sex and age at colonoscopy. The identification of such cumulative models could be valuable in better defining a group of persons, within a given population, that are most likely to benefit from screening for colorectal cancer.

Background For a decade researchers have been searching for modifier genes in individuals with a molecular diagnosis of Lynch syndrome but the task has proven difficult as discordant results seem to be the rule rather than the exception. Recently, two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome patients irrespective of which gene was mutated. In a combined study of CRC risk in Australian and Polish Lynch syndrome patients only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three datasets was performed to better define this association.

Introduction It has not been established whether CHEK2 and NOD2 variants are present in Latvia and whether inherited variation in these genes influences cancer risk in this population. Aim of the study To evaluate the role of CHEK2 and NOD2 mutations in breast and colorectal cancers in the population of Latvia. Materials and methods Peripheral venous blood samples were collected from 185 breast cancer and 235 colorectal cancer consecutive hospital-based cases from 11/2003 to 06/2005. The population control group included blood samples from the clamped distal part of the umbilical cord from 978 consecutive anonymous newborns born between 03/2005 and 08/2005. All cases and controls were tested for the presence of NOD2 3020insC mutation and CHEK2 I157T mutation. Results NOD2 3020insC was present in 7.7% (18/235) of CRC cancers, in 9.2% (17/185) of breast cancers and in 7.7% (75/974) of controls. CHEK2 I157T variant was found in 7.6% (14/185) of breast cancer cases, 10.2% (24/235) of colon cancer cases and in 6.4% (63/978) of population controls. NOD2 3020insC variant was associated with increased risk of breast cancer (OR = 2.5, p < 0.05) for cases diagnosed at age between 51 and 60 years. CHEK2 I157T variant was associated with increased risk of colorectal cancer (OR = 1.7, p < 0.05) with the highest OR = 2.0 for cases diagnosed at age >70 yrs. Conclusions NOD2 3020insC, CHEK2 I157T variants may be associated with increased risk of colorectal and breast cancers in Latvia.