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Expansion of an unstable trinucleotide (CAG)(n) repeat region within exon 1 of the gene IT15 causes autosomal, dominantly inherited Huntington's disease (HD). The number of CAG-repeats varies from 6 to 35 in normal individuals, whereas in affected patients the expanded allele contains 40 or more CAG-repeats. Thus, exact determination of both alleles of the gene (normal and expanded) on the molecular level is of great importance for clinical diagnosis and prognosis regarding the course of the disease. In our study, we optimized and evaluated a highly sensitive, automated, and economical molecular method for length characterization of the trinucleotide fragment expansion such as (CAG)(n) repeat region based on ion-pair reversed-phase high-performance liquid chromatography (IP-RP-HPLC). We found that IP-RP-HPLC can be used for exact fragment length measuring between 60-280 bp as a sensitive and advantageous alternative method to conventional techniques.

Several genome-wide searches for common cancers have lead to the identification of a small number of loci that harbor low-risk cancer susceptibility markers. One marker, rs6983267 on chromosome 8q24, has been linked to both colon and prostate cancer, and is therefore a good candidate for a multicancer susceptibility marker. To determine the range of cancer sites associated with rs6983267, we genotyped 7,665 cases of cancer, representing 11 common cancer sites, and 1,910 controls. A significant odds ratio (OR) was observed for prostate cancer for carriers of genotype GG [OR, 1.77; 95% confidence interval (CI), 1.47–2.13]. The homozygote OR was higher for tumors with Gleason score 8 to 10 (OR, 1.94; 95% CI, 1.18–3.20) than for tumors with Gleason score 7 and below (OR, 1.65; 95% CI, 1.31–2.08). Significantly elevated (homozygote) ORs were observed for 4 other cancer sites, including colon (OR, 1.36; 95% CI, 1.08–1.72), kidney (OR, 1.52; 95% CI, 1.12–2.05), thyroid (OR, 1.37; 95% CI, 1.02–1.82), and larynx (OR, 1.39; 95% CI, 1.02–1.90). Information was available on family histories of cancer for eight sites. For six of the eight sites (prostate, breast, bladder, larynx, lung, and kidney), the homozygote ORs were higher for cases with a positive family history (at least one first-degree with any cancer) than for cases with unaffected first-degree relatives. Our results suggest that the range of cancers associated with the rs6983267 marker might be larger than previously thought. [Cancer Res 2008;68(23):9982–6]

Ports are more and more often applied with patients requiring the permanent intravenous access, not only in the cancer treatment. Very devices, as well as procedures associated with applying them are determined in the heterogeneous way. Therefore during the last conference "Intravenous Port--implantation, care, complications" an attempt to systematize the applied terminology was made.

Mutant alleles of several genes in the DNA repair pathway have been found to predispose women to breast cancer. From a public health perspective, the importance of a given allele in a population is determined by the frequency of the allele and by the relative risk of breast cancer that it confers. In Poland founder alleles of the BRCA1, CHEK2 and NBS1 genes have been associated with an increased risk of breast cancer, but the relative contribution of each of these alleles to the overall breast cancer burden has not yet been determined. We screened 2012 unselected cases of breast cancer and 4000 population controls for 7 different mutations in these genes. Overall, a mutation was found in 12% of the cases and in 6% of the controls. Mutations in BRCA1 and CHEK2 contributed in approximately equal measure to the burden of breast cancer in Poland. A BRCA1 mutation was present in 3% of the cases. The missense BRCA1 mutation C61G was associated with a higher odds ratio for breast cancer (OR=15) than were either of the truncating BRCA1 mutations 4153delA (OR=2.0) and 5382insC (OR=6.2). In contrast, a higher odds ratio was seen for truncating CHEK2 mutations (OR=2.1) than for the missense mutation I157T (OR=1.4). This study suggests that cancer risks may be specific for particular alleles of a susceptibility gene and that these different risks should be taken into account by genetic counselors.

Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast–ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast–ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast–ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. © 2004 Wiley-Liss, Inc.

Variants in the CHEK2 have been found to be associated with prostate cancer risk in the United States and Finland. We sequenced CHEK2 gene in 140 Polish patients with prostate cancer and then genotyped the three detected variants in a larger series of prostate cancer cases and controls. CHEK2 truncating mutations (IVS2 + 1G>A or 1100delC) were identified in 9 of 1921 controls (0.5%) and in 11 of 690 (1.6%) unselected patients with prostate cancer [odds ratio (OR) = 3.4; P = 0.004]. These mutations were found in 4 of 98 familial prostate cases (OR = 9.0; P = 0.0002). The missense variant I157T was also more frequent in men with prostate cancer (7.8%) than in controls (4.8%), but the relative risk was more modest (OR = 1.7; P = 0.03). I157T was identified in 16% of men with familial prostate cancer (OR = 3.8; P = 0.00002). Loss of the wild-type CHEK2 allele was not observed in any of prostate cancers from five men who carried CHEK2-truncating mutations. Our results provide evidence that the two truncating mutations of CHEK2 confer a moderate risk of prostate cancer in Polish men and that the missense change appears to confer a modest risk.

Several predispositions to colorectal cancer have been identified, but little is known about genetic susceptibilities to disease in older persons. Colorectal cancer is a risk in Crohn’s disease and is believed to be associated with an inappropriate inflammatory response. Recently, the NOD2 gene has been associated with Crohn’s disease, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the NOD2 gene, which appear with significantly higher frequency in patients with the disease. One such mutation (3020insC) is believed to be clearly causative because it results in a prematurely truncated protein with a predicted reduction in functional efficiency. In this report, we have examined the frequency of the 3020insC mutation in a series of 856 individuals including 556 patients with colorectal cancer. The frequency of the 3020insC mutation in a consecutive series of 250 non-hereditary nonpolyposis colorectal cancer patients >50 years of age was significantly elevated compared with the control population (odds ratio, 2.23; P = 0.0046). The results indicate that NOD2 may be a predisposing factor to colorectal cancer characterized by an older average age of disease onset in persons who do not harbor any other genetic predisposition to disease.

In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin; a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives; and a series of 530 consecutive individuals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years; in 3 of 80 familial breast cancer cases (3.7%); and in 3 of 530 individuals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients. © 2003 Wiley-Liss, Inc.

Allele variants of the CHEK2 gene have been found to be associated with several types of cancer, including cancer of the breast, prostate, lung, and ovary. In the Polish population, three founder mutations of CHEK2 have been identified: I157T, 444+1G>A (formerly IVS2+1G>A), and 1100delC. The aim of our study was to establish a simple method to identify founder CHEK2 mutations and determine the prevalence of these changes in the population of Eastern Germany (Saxony, Saxony-Anhalt, and Thuringia). We drew up denaturing high-performance liquid chromatography (DHPLC) conditions for analysis of intron 2 and exon 3 for two mutations (444+1G>A, I157T) and exon 10 for mutation 1100delC. We tested 251 patients and controls. Mutations show a similar frequency in the general population of Eastern Germany as in neighboring Poland (4.95% vs. 4.8% for the missense mutation I157T and 0.99% vs. 0.5% for the truncating mutations 444+1G>A and 1100delC). Investigation of these mutations by DHPLC is highly sensitive and less time-consuming compared to restriction fragment length polymorphism or allele-specific oligonucleotide polymerase chain reaction. It can be easily integrated into diagnostic testing.

ARLTS1 – a member of ADP-ribosylation factor family, is a newly described candidate tumour suppressor gene. Recent studies show that a nonsense polymorphism, G446A (Trp149Stop), in ARLTS1 gene is significantly more frequent in familial cancer cases than in sporadic cancer cases. This study presents analysis of the germ-line G446A polymorphism in the ARLTS1 gene among 1686 consecutively collected patients with breast cancer, prostate cancer, malignant melanoma, thyroid papillary cancer or laryngeal cancer in Poland. The G446A allele was present in 1.81% (9/497) breast cancer patients, 1.46% (5/343) prostate cancer patients, 1.76% (7/397) melanoma patients, 1.65% (3/182) thyroid papillary carcinoma patients and 2.68% (8/299) of laryngeal cancer patients. The frequency of this polymorphism in the control group was 1.45% (8/552). Differences in the frequency of the G446A polymorphism between case and control groups were not statistically significant. In addition, there was no significant difference in the number of Cancer Familial Aggregations (CFA) among breast, prostate, thyroid or laryngeal cancer cases harbouring the G446A polymorphism, when compared to the G446A negative cases. Interestingly out of the CFA melanoma cases, 4/6 (66.6%) were found to harbour the change compared to only 20.2% (69/341) sporadic melanoma cases. This difference was statistically significant (p = 0.02, OR = 7.8). The results of this study suggest that the G446A in ARLTS1 gene is probably not associated with an increased risk of sporadic breast cancer, prostate cancer, melanoma, thyroid papillary cancer or laryngeal cancer. Moreover, the G446A polymorphism is not significantly more frequent in CFA cases except for families in which the proband had melanoma. To confirm this result more cases of melanoma should be analysed.

The population frequencies of the CDKN2A common variants remain undetermined. In Poland, there is a common variant of the CDKN2A: an alanine to threonine substitution (A148T), which has been detected in other populations. We have recently showed that it is significantly overrepresented among Polish melanoma patients when compared to general population. Herein, we ascertained the prevalence of the A148T variant in 3,583 unselected cancer cases and 3,000 random control subjects from the same Polish population. We evaluated eleven different malignancies, representing the majority of all common cancer sites. Positive association with A148T variant was observed for lung cancer (OR, 2.0; p = 0.0052). A similar trend, although nonsignificant after the Bonferroni correction, was observed for colorectal cancer (OR, 1.5; p = 0.5499). These results suggest that A148T variant may be associated with a multi-organ cancer risk in the Polish population.

Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention.

In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin; a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives; and a series of 530 consecutive individuals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years; in 3 of 80 familial breast cancer cases (3.7%); and in 3 of 530 individuals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients.

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.

The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles.

Keywords: CDKN24, CHEK2, NOD2, cancer risk There is continuing interest in identifying low-penetrance genes which are associated with increased susceptibility to common types of cancer. There are several approaches to this problem, including the use of chip-based single nucleotide polymorphism (SNP) arrays to interrogate a large number of genes simultaneously and pre-selecting candidate genes of interest. Candidate genes for cancers of a particular site may be selected because they are known to predispose to malignancies of other organs, or because they are mutated somatically in the cells from the cancer of interest. It is possible that missense variants of genes for which truncating mutations are clearly pathogenic may also be deleterious, but with reduced penetrance. In this situation the association may be overlooked unless large numbers of cancers are studied. In our centre we performed population-based studies of common variants of three genes: a tumour-suppressor gene CDKN2A (OMIM 600160), NOD2 (OMIM 605956) involved in the chronic inflammation process, and CHEK2 (OMIM 604373) participating in the DNA damage response. To determine whether CDKN2A common variant A148T may be associated with an increased risk of malignancies at different sites of origin we genotyped a series of 8,263 unselected cancer cases and compared the frequency of the change observed in this population to 3,000 controls in Poland. To establish the range of cancer types associated with three CHEK2 mutations (VS2+1G → A, 1100delC, and I157T) we genotyped 4,008 unselected cases of cancer and 4,000 controls in Poland. In order to define the range of cancer phenotypes associated with the NOD2 3020insC mutation we examined 2,604 unselected invasive cancers of 12 different types and 1,910 controls from Poland.