Cumulative effects of genetic markers and the detection of advanced colorectal neoplasias by population screening.

Genetic markers associated with colorectal cancer may be used in population screening for the early identification of patients at elevated risk of disease. We genotyped 3059 individuals with no cancer family history for eight markers previously associated with colorectal cancer. After colonoscopy, the genetic profile of cases with advanced colorectal neoplasia (213) was compared with the rest (2846). rs2066847 and rs6983267 were significantly associated with the risk of advanced colorectal neoplasia but with limited effect on their own [odds ratio (OR) 1.59; 95% confidence interval (CI) 1.02-2.41; p = 0.033 and OR 1.45; 95% CI 1.02-2.12; p = 0.044, respectively]. Cumulative effects, in contrast, were associated with high risk: the combination of rs2066847, rs6983267, rs4779584, rs3802842 and rs4939827 minimized the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it, for example, for at least two cumulated risk markers, OR is 2.57 (95% CI 1.50-4.71; corrected p-value 0.0079) and for three or more, OR is 3.57 (95% CI 1.91-6.96; corrected p-value 0.00074). The identification of cumulative models of - otherwise - low-risk markers could be valuable in defining risk groups, within an otherwise low-risk population (no cancer family history).

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband.

It is important to have accurate knowledge of the range of cancers associated with various CHEK2 mutations, and of the lifetime risks of cancer associated with each. We wished to establish the relationship between family history, mutation type and cancer risk in families with a CHEK2 mutation. We obtained a blood sample and pedigree information from 2012 unselected women with breast cancer, from 2007 men with prostate cancer and from 1934 patients with colon cancer, from hospitals throughout Poland. Genetic testing was carried out for four founder CHEK2 mutations on all 5953 specimens and 533 carriers were identified. We estimated the risk to age 75 for any cancer in the 2544 first-degree relatives to be 22.3%. After adjusting for mutation type, the risk of breast cancer was much higher among relatives of probands with breast cancer than among relatives of patients with prostate or colon cancer (HR=3.6; 95% CI=2.1-6.2; P=0.0001). Similarly, the risk of prostate cancer was higher among relatives of probands with prostate cancer than among relatives of patients with breast or colon cancer (HR=4.4; 95% CI=2.2-8.7; P=0.0001) and the risk of colon cancer was higher among relatives of probands with colon cancer than among relatives of patients with prostate or breast cancer (HR=4.2; 95% CI=2.4-7.8; P=0.0001). These analyses suggest that the risk of cancer in a carrier of a CHEK2 mutation is dependent on the family history of cancer.

The -149C>T SNP within the DeltaDNMT3B gene, is not associated with early disease onset in hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited syndrome caused by germline mutations in mismatch repair (MMR) genes. HNPCC patients have a lifetime risk of 80% of developing colorectal cancer (CRC); however the likely age of onset is difficult to predict. A single C>T polymorphism located within the promoter region of the DeltaDNMT3B gene has recently been reported to be associated with a significant increase to the risk of early onset CRC. In this study we determined the DeltaDNMT3B genotype in 404 confirmed HNPCC participants (total of 194 CRC cases) from Australia (203) and Poland (201). From the total number of participants there were 194 diagnosed cases of CRC and 210 healthy MMR gene mutation carriers. The study was undertaken to assess whether the reported effect observed in a previous study of 146 HNPCC patients is consistent in a larger separate and unrelated participant cohort. Through the statistical tests of Kaplan-Meier survival analysis and Cox hazard regression models we did not observe any significant association between the DeltaDNMT3B C>T SNP and early onset CRC in HNPCC patients.

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

NOD2 variants and the risk of malignant melanoma.

Both hereditary and environmental factors are important in the aetiology of malignant melanoma. Among the risk factors for malignant melanoma are immunodeficiency and immunosuppression. The recently identified NOD2 gene is involved in the regulation of immune function through activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Three common NOD2 mutations -- 3020insC, G908R and R702W -- have been shown to be associated with chronic inflammatory disease such as Crohn's disease, the 3020insC also with human malignancy colorectal cancer. We examined the frequency of the NOD2 variants in 424 patients with malignant melanoma and 649 controls. The 3020insC mutation was present in 6.9% of unselected cases and 7% of the controls (odds ratio (OR) 1.0; P not significant). The mutation was present in 6.8% of 162 cases diagnosed under the age of 50 and in 7.1% of cases diagnosed after the age of 50. A mutation was present in the index case in 5% of 40 familial melanomas (OR 0.7; P not significant). There were no statistically significant differences between prevalence of G908R and R702W in malignant melanoma patients and controls. In conclusion, the three common NOD2 mutations are not associated with increased risk of development of malignant melanoma.

CHEK2 is a multiorgan cancer susceptibility gene.

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.

[Effectiveness of oral administration of ivermectin on warble fly larvae (Hypoderma diana B.) in roe deer]. / Ucinnost perorálne podaného ivermektinu proti larválním stadiím strecka srncího (Hypoderma diana B.) u srncí zvere.

Hypodermosis and cephenemyiosis are largely widespread diseases in roe deer in the conditions of the Czech Republic. Both kinds of parasitosis cause great losses of game. The aim of this study was to test peroral administration of ivermectin with respect to the control of larval stages of hypodermosis (Hypoderma diana B.) in roe deer. Studies were performed on three localities within one three-year study and two 18-month studies. Ivermectin was administered for two days at a daily dose of 0.30 mg/kg body weight during winter game feeding. The shot deer were checked for the presence of larvae throughout the year. Prevalence and intensity of infection were determined. A total of 147 animals were checked in 1992-1994 (Tab.I); prevalence and intensity of infection were very low in comparison with the situation before treatment and with the control group (1994). Similar results were obtained in both shorter studies (Tab. II) performed on 27 animals in total. The results suggest (on the base of detail discussion) that the low values of prevalence and intensity of infection should be taken as partly distorted due to the methodical conditions of checks. The efficacy of ivermectin treatment was complemented by observation of several cases and their results employing direct checks of shot deer (Tab. III), including a six-year observation of a group of 6 to 10 individuals of tame deer treated year by. These results explicitly document the high efficacy of mass peroral ivermectin administration in the control of warble fly larvae. Ivermectin is the first drug suitable for the treatment of roe deer hypodermosis.

Blood groups of Roms (Gypsies) in Czechoslovakia.

Blood groups in 2,935 Roms (Gypsies) of East Slovakia show the following frequencies of phenotypes and genes: A1A2BO phentopes: A1--32.91%, A2--2.42%, B--25.21%, O--30.15%, A1B--8.45%, A2B--0.85%, A1--0.2363, A2--0.0217, B--0.1929, O--0.5491. MN phenotypes: M--27.16%, MN--51.60%, N--21.23%, m--0.5297, n--0.4703. RH phenotypes: Rh positive--89.54%, Rh negative--10.46%; Rh - (D)--0.6766, Rh (d) 0.3234. The frequencies are contrasted with those of other inhabitants, non-Roms of East Slovakia.