Gene expression profiles in three histologic types, clear-cell, endometrioid and serous ovarian carcinomas.

Ovarian carcinoma is the most lethal type of gynecologic malignancy in the Western world. Majority of early stage ovarian cancers are asymptomatic and this is the main reason that more than two-thirds of patients are diagnosed with advanced disease. Ovarian tumors are heterogeneous and the different histologic subtypes are further classified as benign, borderline (low-grade) and malignant (high-grade) to reflect their behavior. The aim of the study was to analyze gene expression profiles in three histologic types of ovarian carcinoma in an attempt to find the molecular differences among serous, endometrioid and clear cell subtypes. The analysis of gene expression was performed on 57 samples of ovarian carcinoma. RNA was isolated from the ovarian cancer tissues. The gene expression changes were determined by microarray analysis and quantitative real time polymerase chain reaction (qRT-PCR). Measurement of relative gene expression levels was used to identify molecular differences among three histologic types of ovarian carcinoma (clear-cell, endometrioid and serous). Unsupervised statistical analysis revealed four biological subtypes among three histotypes under study. The endometrioid ovarian carcinoma was divided into two molecular subtypes. The biggest molecular differences were observed between clear-cell and serous carcinomas (1070 genes, FDR 0.05), the smallest between endometrioid and serous carcinomas (81 genes, FDR 0.05). The biggest group of differentially expressed genes was involved in transport and metabolism. This finding can explain the differences in the response to chemotherapy observed among different histologic types of ovarian carcinomas. In conclusion, we found TCF2 (HNF1B) gene as a suitable marker for ovarian clear cell carcinoma. Gene expression profiling also shed light on the molecular mechanisms of different chemoresistance among the analyzed histotypes.

Combined effect of low-penetrant SNPs on breast cancer risk.

BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status. METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression. RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)). CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations.

OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.

Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers.

PURPOSE: There have been no studies to date which look at the relative effectiveness of different regimens of chemotherapy in women who have breast cancer and who carry a BRCA1 germ-line mutation. We wished to compare rates of response to neo-adjuvant chemotherapy in BRCA1 mutation carriers and non-carrier controls. EXPERIMENTAL DESIGN: From a registry of 3,479 patients, we identified 44 Polish women who carried a BRCA1 founder mutation and who had been treated with neo-adjuvant chemotherapy for breast cancer, and 41 age- and hospital-matched controls. RESULTS: 35 of the 44 BRCA1 mutation carriers (80%) experienced a partial or complete response to neo-adjuvant chemotherapy, compared to 39 of the 41 (95%) non-carriers (P=0.05). In the hereditary subgroup, response rates differed depending on whether or not a taxane (docetaxel) was given. Six of the 15 BRCA1 carrier women given docetaxel with doxorubicin responded (complete or partial), compared to 29 of 29 given other (DNA-damaging) therapies (P=0.001). Among the non-carriers, the rates of response to the two categories of chemotherapy were similar. CONCLUSIONS: Breast cancers among BRCA1 carriers frequently do not exhibit sensitivity to docetaxel in the neo-adjuvant setting. It is likely that normal BRCA1 is required for clinical response to mitotic spindle poisons.

Coronary artery calcification, common carotid artery intima-media thickness and aortic pulse wave velocity in patients on peritoneal dialysis.

An increasing body of evidence suggests that atherosclerosis in patients with uremia differs from that found in general population in terms of advancement and localization of vascular lesions. It has also been suggested that different non-invasive techniques of vascular system evaluation are designed to show different types of lesions (i.e. vascular calcification, stiffness or 'classical' atherosclerosis). The aim of the study was to search for possible associations between results obtained with three different non-invasive methods of vascular system assessment in three different vascular sites in patients treated with peritoneal dialysis (PD). 61 patients (28 F, 33 M), mean age of 50.4+/-13.6 years, on maintenance PD for a median period of 10 months (range 1-96 months) were included. Coronary artery disease (CAD) was present in 21 subjects. In all subjects coronary artery calcification score (CaSc) using multi-row spiral computed tomography (MSCT), aortic pulse wave velocity (AoPWV) and ultrasound-based common carotid artery intima-media thickness (CCA-IMT) were performed as methods for assessing coronary calcium burden, arterial stiffness and atherosclerosis, respectively. Median value of CaSc equaled 11.5 Agatston units (range 0-5502.8 units). Median AoPWV was 10.4 m/s (range 7.56-18.1 m/s), and median CCA-IMT-0.6 mm (range 0.3-1.0 mm). In 16 patients (26.2%) at least one plaque in at least one common carotid artery was found on ultrasound. CaSc correlated with AoPWV (R=0.32, p<0.01) and with CCA-IMT (R=0.35, p<0.005), whereas no association was found between AoPWV and CCA-IMT. AoPWV, but not CaSc nor IMT correlated with blood pressure. The values of CCA-IMT and AoPWV increased together with consecutive Agatston categories (with p<0.001 for differences in AoPWV and p<0.05 for CCA-IMT). Patients with at least one plaque found in at least one CCA and patients with CAD were characterized with significantly higher values of CaSc, IMT and PWV, when compared to plaque-free and CAD- negative subjects, respectively. Association between CaSc and both IMT and PWV may suggest that the mechanism of three assessed vascular pathologies may be based, to some extent, on the process of pathologic calcium-phosphate deposition. Lack of correlation found between PWV and IMT may suggest that aortic stiffness and carotid atherosclerosis may partially differ in their pathologic background and/or are dissociated in time.

XPD common variants and their association with melanoma and breast cancer risk.

There are suggestions in the literature that common variants in the XPD gene may be associated with an altered risk of melanoma and breast cancer. To establish if the XPD common variants Asp312Asn and Lys751Gln are associated with an increased melanoma or breast cancer risk we performed an association study based on genotyping 426 unselected patients with malignant melanoma (MM) and 1830 consecutive breast cancer cases and compared the results to 1262 geographically matched newborns, 621 adults from the region of Szczecin (unselected for age and cancer family history), 421 healthy adults age- and sex-matched with the melanoma cases and 511 healthy controls matched with the breast cancer patients from the region of Szczecin. Additionally we examined the prevalence of three additional XPD variants, Gly156Gly, Leu485Pro and Arg112His amongst the 421 unselected melanoma patients. All of the variants when evaluated singularly were found not to be associated either with melanoma or breast cancer risk in younger or older patients. A modest association was observed with breast cancer risk when the Lys751Gln_CC/Asp312Asn_AA genotype (OR=1.5, p<0.05) segregated together. Individuals harboring the Lys751Gln_CC/Gly156Gly_CC genotype were significantly over-represented among late-onset melanoma cases (OR=1.7, p<0.05). The results of analyses of linkage disequilibrium and haplotype frequency support the thesis that a combination of at least two SNPs (Lys751Gln_CC/Gly156Gly_CC or Lys751Gln_CC/Asp312Asn_AA) inherited as a haplotype was associated with disease. These two pairs of SNPs could therefore be regarded as a single hereditary unit that would have a very small probability of being disrupted by recombination. Additional studies are required to determine whether these particular changes can be associated with an increased risk of other malignancies at different sites of origin.

BRCA1-positive breast cancers in young women from Poland.

We identified 4316 unselected incident cases of early-onset breast cancers (<51 ears of age at diagnosis) in 18 Polish hospitals between 1996 and 2003. We were able to obtain a blood sample for DNA analysis from 3472 of these (80.4%). All cases were tested for the presence of three founder mutations in BRCA1. The proportion of cases with a BRCA1 mutation was 5.7%. The hereditary proportions were higher than this for women with breast cancer diagnosed before age 40 (9%), for women with cancer of medullary or atypical medullary histology (28%), for those with bilateral cancer (29%) or with a family history of breast or ovarian cancer (13%). It is reasonable to offer genetic testing to women with early-onset breast cancer in Poland.

Association of polymorphisms and haplotypes in the human growth hormone 1 (GH1) gene with breast cancer.

The growth hormone 1 (GH1)/insulin-like growth factor I (IGF-I) axis plays an important role in the development of breast cancer. By binding to its receptor, GH1 stimulates the production of IGF-I and its binding protein IGFBP3, resulting in the regulation of cell proliferation, differentiation and apoptosis. The GH1 gene expression is regulated by a highly polymorphic proximal promoter and a distal locus control region (LCR) 14.5 kb upstream of the gene. We investigated the effect of single nucleotide polymorphisms (SNPs) in the LCR and in the promoter region and an intron 4 SNP (IVS4+90 T/A) on breast cancer risk in a large cohort of Polish and German familial breast cancer cases and controls. SNPs in the LCR did not show an influence on breast cancer risk, either alone or in haplotypes. Three SNPs in the promoter region (G-340T, A-68G/C and A-63T/C) showed an increased and four SNPs (A-137G, G-119T, G-93delG and T-4G) a decreased allele frequency in the cases compared with the controls. Two of the SNPs (A-137G and G-93delG) lead to a decreased breast cancer risk among the minor allele carriers in the joint analysis of the two populations (odds ratio (OR) 0.62, 95% confidence interval (95% CI) 0.44-0.89, P = 0.01 and OR 0.65, 95% CI 0.47-0.90, P = 0.01, respectively). Haplotype analysis with these seven promoter SNPs revealed a protective association (OR 0.61, 95% CI 0.37-1.00, P = 0.04) for the haplotype GAGdAAT, containing the G-93delG variant allele, which in the single analysis already showed a protective effect. The effect was marginally stronger in combination with the LCR GC haplotype (OR 0.49, 95% CI 0.23-1.01, P = 0.04).

A common variant of CDKN2A (p16) predisposes to breast cancer.

BACKGROUND: A common missense variant of the CDKN2A gene (A148T) predisposes to malignant melanoma in Poland. An association between malignant melanoma and breast cancer has been reported in several families with CDKN2A mutations, OBJECTIVE: To determine whether this variant also predisposes to breast cancer. METHODS: Genotyping was undertaken in 4209 cases of breast cancer, unselected for family history, from 18 hospitals throughout Poland and in 3000 controls. RESULTS: The odds ratio (OR) associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 (p = 0.002) and after age 50 it was 1.3 (p = 0.2). The effect was particularly strong for patients diagnosed at or before the age of 30 (OR = 3.8; p = 0.0002). CONCLUSIONS: CDKN2A appears to be a low penetrance breast cancer susceptibility gene in Poland. The association should be confirmed in other populations.

BRCA1 and BRCA2 mutations as prognostic factors in bilateral breast cancer patients.

BACKGROUND: Incidence of primary bilateral breast cancer (BC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer (53% versus 2%). PATIENTS AND METHODS: A group of 108 patients with bilateral breast cancer, who reported at our Cancer Centres from 2000 to 2002, were subjected to genetic testing. Similarities and differences between BRCA1/2 carriers and non-carriers were analysed in terms of family history, pathology of tumour, age of diagnosis, developing contralateral BC and second primary cancer. RESULTS: BRCA1/2 mutations were detected in 32 of 108 patients. Family history of BC was identified in 46.9% of these patients compared with 22.4% of non-carriers (P <0.05). Synchronous BC was diagnosed significantly rarer [4 of 32 (12.5%)] in BRCA1/2 carriers than in the non-carrier group [26 of 76 (34.2%)]. In addition, patients with BRCA mutations were younger when they were diagnosed than non-carriers. BRCA1/2 carriers had a significantly higher incidence of medullary BC (13.6% versus 1.7%) and developed ovarian cancer significantly more frequently than non-carriers (12 of 32 and 1 of 72 patients, respectively). CONCLUSIONS: Patients with bilateral BC having BRCA mutations are significantly younger than non-carriers. They also have a significantly higher family history of BC and an increased risk of developing ovarian cancer. The differences in clinical aspects of BRCA carriers with bilateral BC should be considered in clinical management.

An association between aortic pulse wave velocity, blood pressure and chronic inflammation in ESRD patients on peritoneal dialysis.

Increased aortic pulse wave velocity (AoPWV) has been identified as a risk factor for cardiovascular morbidity in the general population and in patients on dialysis. Most of the studies in ESRD patients refer to subjects on hemodialysis. Influence of the inflammatory process on aortic stiffening remains largely unknown. The aim of the present study was to evaluate potential relationships between AoPWV and blood pressure, basic anthropometric parameters, selected growth factors and markers of the inflammatory process in ESRD patients treated with peritoneal dialysis. The study population consisted of 43 patients (19 F, 24 M) with a mean age of 50.6 +/- 13.4 years on PD for a mean period of 21.9 +/- 20.7 months. AoPWV was measured using two pressure transducers placed on the carotid and femoral arteries and connected to an automatic processor (Complion Colson AS, Paris, France). Serum levels of Tumor Necrosis Factor alpha (TNFalpha), interleukin 6 (IL-6) and plasma basic Fibroblast Growth Factor (bFGF) were measured with ELISA; C-reactive protein and fibrinogen with nephelometry. Serum lipid profile was also assessed. Blood pressure was measured in an outpatient department under standardized conditions. Mean aortic pulse wave velocity in the study population was 10.7 +/- 2.1 m/s. No difference in AoPWV was found between men and women. AoPWV correlated significantly with age (R = 0.41; p < 0.01) but not with time on dialysis. Positive relationship between AoPWV and body weight and BMI was shown (R = 0.31; p < 0.05 and R = 0.35; p < 0.05, respectively). AoPWV correlated significantly with systolic blood pressure (SBP), mean arterial pressure (MAP) and pulse pressure (PP) (R = 0.46, p < 0.005, R = 0.46, p < 0.005 and R = 0.43, p < 0.01, respectively). AoPWV correlated with serum IL-6 and plasma bFGF (R = 0.32, p < 0.05 and R = 0.4, p < 0.01; respectively). The correlation with serum CRP was borderline significant (p < 0.53). In multiple regression analysis age (beta 0.38; p < 0.005), plasma bFGF level (beta 0.3; p < 0.05), and systolic blood pressure (beta 0.29; p < 0.05) were independently associated with pulse wave velocity. Our results suggest that AoPWV values in patients on PD are associated with factors similar to those encountered in the general population. We suggest that increased aortic stiffening may also be related to the chronic inflammatory process in PD patients.

[Urological complications in patient after kidney transplantation. Correction of ureter stenosis with consequent proper renal graft function]. / Pacjentka po przeszczepieniu nerki z powiklaniem urologicznym. Skuteczna korekta zwezonego moczowodu z nastepowa dobra funkcja przeszczepu.

Urological complications constitute significant problem following renal transplantation. Incidence ranges from 4 to 14% in graft recipients. The most important aspects concerning these complications are early diagnosis and prompt treatment, any delay in diagnosis and management may lead to deterioration of renal graft function or graft loss. The following case report discusses management of hydronephrosis in renal graft caused by ureter stenosis due to scarring and fibrosis of its distal end after remote kidney transplantation. The patient was a 33-year-old woman with previous history of end stage renal failure in the course of chronic glomerulonephritis. A triple drug immunosuppressive regimen consisting of Azathioprine (AZT), Cyclosporine A and Encorton (AZT + CsA + Encorton) was administered during a period of three years after kidney transplantation. At this time AZT administration was discontinued due to chronic viral hepatitis type B. Episodes of expansion sensation (discomfort) and graft pain were reported by the patient which after 3 days were followed by a period of oliguria and then anuria. The patient was admitted to the Department of Nephrology CMUJ, where ultrasound imaging revealed graft hydronephrosis. In the presence of such clinical and biochemical indications due to acute graft failure, one hemodialysis session, was performed. The patient was transferred to the Urological Department CMUJ where ureter exploration was attempted, but was unsuccessful. Subsequently percutaneous nephrostomy was performed which lead to immediate diuresis. Next, distal ureter stenosis (located by the urinary bladder) was surgically removed and reimplantation of the ureter was carried out. Due to early diagnosis and surgical reconstruction of the transplanted ureter, renal graft function returned to normal requiring only one hemo-dialysis session.

The effect of the genetic polymorphisms of CYP1A1,CYP2D6, GSTM1 and GSTP1 on aromatic DNA adduct levels in the population of healthy women.

Aromatic DNA adduct levels and polymorphisms of two phase I enzymes - CYP1A1 and CYP2D6 and two phase II enzymes - GSTM1 and GSTP1 were analyzed in a group of 133 nonsmoking healthy women 35-45 years old and holding jobs not connected with the exposure to the combustion products of organic matter. They were office workers from the south and north-eastern parts of Poland. Blood samples were collected in winter and in summer. Aromatic DNA adduct levels were measured in all winter and summer samples. The frequencies of CYP1A1, CYP2D6, GSTM1 and GSTP1 polymorphisms in samples from the studied women did not show any differences when compared with other Caucasian populations and the Polish male population studied previously. The differences in the levels of DNA adducts among the carriers of different genotypes were statistically non-significant. Analysis of combined genotypes selected the groups of volunteers with the highest and the lowest DNA adduct levels. The highest levels of DNA adducts were observed in the carriers of GSTM1(null)/CYP1A1Ile/Val (8.00+/-13.00 adducts/10(8) nucleotides in summer samples) and GSTP1-AA/CYP1A1Ile/Val genotypes (7.00+/-4.32 in winter and 7.30+/-7. 27/10(8) nucleotides in summer). The lowest levels of DNA adducts (3. 00+/-2.30 in winter and 2.00+/-3.16/10(8) nucleotides in summer) were found in the carriers of the genotype GSTP1-AG+GG/CYP1A1Ile/Val. The levels of DNA adducts in these groups were determined by the polymorphisms of GSTM1 and GSTP1 phase II detoxifying enzymes.

Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.

We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.

Polymorphisms of the GSTP1 and GSTM1 genes and PAH-DNA adducts in human mononuclear white blood cells.

Glutathione S-transferases (GSTs) are an important part of the protection system against a wide range of potentially harmful chemical compounds. GSTP1 and GSTM1 are mainly involved in detoxification reactions of PAH carcinogenic intermediates produced by cytochrome P450 (CYP). Polymorphism of the GST genes may influence the level of carcinogen-DNA adducts in human tissues and be associated with individual susceptibility to carcinogens. In this study, we examined the effect of common polymorphism in exon 5 (105Ile --> Val) of the GSTP1 gene, alone and in combination with GSTM1-deletion polymorphism, on the level of PAH-DNA adducts measured by (32)P-postlabeling assay in mononuclear white blood cells collected in winter and in summer from a total of 170 healthy volunteers. When GSTP1 genotypes alone were compared, no statistically significant differences in adduct levels were found. However, smokers with GSTM1(null)/GSTP1-AG or -GG combined genotype showed significantly higher adduct levels in summer than carriers of other GSTM1/GSTP1 combinations (5.60 +/- 5.10 vs. 3.45 +/- 4. 28/10(8) nucleotides, P = 0.015). Among smokers carrying GSTP1-AG or -GG genotype, individuals with GSTM1(null) genotype had a significantly higher level of adducts in summer than subjects with GSTM1(+) genotype (5.60 +/- 5.10 vs. 1.82 +/- 1.98/10(8), P = 0.002) and GSTM1(null)/GSTP1-AA genotype carriers (5.60 +/- 5.10 vs. 4.13 +/- 5.84/10(8), P = 0.03). When adduct levels measured either in winter or in the nonsmoker group were considered, no influence of GSTM1/GSTP1 genotypes was found. Our data show that the combined GSTM1 and GSTP1 genetic polymorphisms may modulate PAH-DNA adduct levels in mononuclear WBCs from individuals exposed to specific carcinogenic compounds, e.g., tobacco smoke, in relatively lower-exposure environmental conditions (i.e., in summer).

High frequency of recurrent mutations in BRCA1 and BRCA2 genes in Polish families with breast and ovarian cancer.

Germ-line mutations in BRCA1 and BRCA2 genes result in a significantly increased risk of breast and ovarian cancer. Other genes involved in an increased predisposition to breast cancer include the TP53 gene, mutated in Li-Fraumeni syndrome. To estimate the frequency of germ-line mutations in these three genes in Upper Silesia, we have analyzed 47 breast/ovarian cancer families from that region. We found five different disease predisposing mutations in 17 (36%) families. Twelve families (25.5%) carried known BRCA1 mutations (5382insC and C61G), four families (8.5%) carried novel BRCA2 mutations (9631delC and 6886delGAAAA), and one family (2%) harbored novel mutation 1095del8 in the TP53 gene, which is the largest germline deletion in coding sequence of this gene identified thus far. The 5382insC mutation in BRCA1 was found in 11 families and the 9631delC mutation in BRCA2 occurred in three families. These two mutations taken together contribute to 82% of all mutations found in this study, and 30% of the families investigated harbor one of these mutations. The very high frequency of common mutations observed in these families can only be compared to that reported for Ashkenazi Jewish, Icelandic, and Russian high-risk families. This frequency, however, may not be representative for the entire Polish population. The observed distribution of mutations will favor routine pre-screening of predisposed families using a simple and cost-effective test.

[Long-term good results of surgical treatment for spontaneous epi- and subdural hematoma in a female patient on maintenance hemodialysis]. / Dlugotrwaly dobry wynik leczenia operacyjnego spontanicznego krwiaka nad- i podtwardówkowego u chorej objetej programem powtarzanych hemodializ.

Spontaneous intracranial hematoma is not rare, but with bad prognosis, complication in patients on maintenance hemodialysis (HD). Diagnostic difficulties result from a fact that symptoms of acute hematoma such as headaches,, nausea, vomitis, apathy, sleepiness, parestesia and seizures may also suggest dysequilibrium syndrome, dialytic dementia as well as hypertensive encephalopathy. We describe a case of female patient with 20-year interview data of hypertension on HD since 1981 because of end-stage renal failure in a course of chronic glomerulonephritis, who developed spontaneous epi- and subdural hematoma four year ago in 47 age of life. Performed CT examination confirmed diagnosis and on the same day the patient underwent right frontoparietotemporal craniotomy and the hematoma was removed. During postoperative period, HD sessions were performed without heparin. After surgery the patient developed transcient hypertonia, epileptic sizures and left-sided paresis. Currently, 48 months after craniotomy the patient is fully rehabilitated, with normal blood pressure, without epileptic sizures or palsy. Gradually we discontinued anticonvulsans and antihypertensives.

Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1 CYP2D6 and GSTM1 genetic polymorphisms.

The CYP1A1, CYP2D6 and GSTM1 genes encode biotransforming enzymes involved in activation and detoxification of xenobiotics. Metabolically activated chemical compounds may interact with DNA and form adducts. In this study, the effect of the GSTM1, CYP1A1 exon 7 and CYP2D6 polymorphisms on DNA adduct levels was studied in 170 healthy volunteers. DNA adducts levels were measured by 32P-postlabelling in mononuclear white blood cells (WBC, lymphocytes and monocytes) and granulocytes collected in summer and winter. The influence of the genotype on the level of DNA adducts in both types of WBCs was observed only in summer samples. Individuals with GSTM1 deficient (null) genotype had significantly elevated level of adducts in mononuclear WBCs (p = 0.045) and granulocytes (p = 0.031) compared to GSTM1 positives. Higher adduct levels in carriers of combined GSTM1(null)/CYP1A1-Ile/Val genotype were found in both types of WBCs when compared to GSTM1(+)/CYP1A1-Ile/Ile genotype carriers (p = 0.046 in granulocytes, p = 0.092 in mononuclear WBCs). CYP2D6 wild-type homozygotes (EMs) and heterozygotes (HEMs) were shown to have significantly higher mononuclear WBC DNA adduct levels than mutant homozygotes (PMs) (p = 0.037 and p = 0.014). When confounding factors associated with PAH exposure were taken into account a statistically significant effect of CYP1A1 exon 7 polymorphism on DNA adduct levels was found (p = 0.012 in mononuclear WBCs, p = 0.043 in granulocytes). In a subgroup of current smokers (n = 95) high DNA adduct levels in granulocytes were associated with GSTM1(null) genotype, and increased adduct levels in mononuclear WBCs correlated with CYP2D6 EM and HEM genotypes. In winter samples the association between the genotype and DNA adduct levels was not observed.