Loss of heterozygosity at BRCA1/2 loci in hereditary and sporadic ovarian cancers.

Loss of heterozygosity at BRCA1/2 loci in breast and ovarian tumors is a suggested risk factor for germline BRCA1/2 mutation status. We evaluated the presence of losses of selected microsatellite markers localized on chromosomes 17 and 13q in hereditary and sporadic ovarian tumors. 151 consecutive primary ovarian tumors (including 21 with BRCA1/2 mutations and 130 without the mutations) were screened for loss of heterozygosity at loci on chromosomes 17 and 13q. Losses of heterozygosity of at least one microsatellite marker localized on chromosomes 17 and 13q were revealed in 123 (81.5%) and 104 (68.9%) tumors, respectively. Losses of all informative markers on chromosomes 17 and 13 occurred in 30 (19.9%) and 31 (20.5%) tumors, respectively. There was no difference in the frequency of losses at BRCA1 intragenic markers (D17S855 and D17S1323) between BRCA1-positive and BRCA1-negative patients. The frequency of losses on chromosome 17 was higher in high-grade than in low-grade carcinomas. Loss of heterozygosity on chromosomes 17 and 13q is a frequent phenomenon in both hereditary and sporadic ovarian cancers. The frequency of losses at BRCA1 intragenic markers in the ovarian tumor tissue is not strongly related to the presence of BRCA1 germline mutations.

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.

Solaria compliance in an unregulated environment: the Australian experience.

This study aimed to explore compliance with international recommendations on solaria use in a unregulated setting. Simulated customers visited 176 solaria operating in Australia and two face-to-face visits and one telephone contact were made for each establishment. From the survey, establishments compliant with the recommendations ranged from: 1.1% refusing access to the customer with skin type I; 9.7% recommending to the customer with skin type I against solaria use and up to 87.5% assessing skin type and recommending eye protection. Few (15.9%) were compliant with more than 10 of the 13 recommendations. Establishment type and number of sunbeds were significantly associated with compliance. This study has shown that a much higher level of compliance with recommendations, particularly those excluding higher-risk groups, is required to reduce the harm associated with use of solaria. While new legislation may be useful, other harm minimisation strategies including mandatory staff training and taxation should be considered.

Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18.

We report the results of detailed clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Classical cytogenetics and fluorescence in situ hybridization (FISH) analysis with the chromosome 18 painting probe identified five non-mosaic and two complex mosaic 46,XX,dup(18)(p11.2)/47,XX,dup(18)(p11.2),+r(18) and 46,XX,dup(18)(p11.32)/47,XX,dup(18)(p11.32),+r(18) cases. FISH analysis was performed for precise characterization of the chromosome 18 breakpoints using chromosome 18-specific short-arm paint, centromeric, subtelomeric, and a panel of fifteen Alu- and DOP-PCR YAC probes. The breakpoints were assessed with an average resolution of approximately 2.2 Mb. In all r(18) chromosomes, the 18q terminal deletions ranging from 18q21.2 to 18q22.3 ( approximately 35 and 9 Mb, respectively) were found, whereas only in four cases could the loss of 18p material be demonstrated. In two cases the dup(18) chromosomes were identified as inv dup(18)(qter-->p11.32::q21.3-->qter) and inv dup(18)(qter-->p11.32::p11.32-->p11.1: :q21.3-->qter)pat, with no evidence of an 18p deletion. A novel inter-intrachromatid mechanism of formation of duplications and ring chromosomes is proposed. Although the effect of "ring instability syndrome" cannot be excluded, the phenotypes of our patients with characteristic features of 18q- and 18p- syndromes are compared and correlated with the analyzed genotypes. It has been observed that a short neck with absence of cardiac anomalies may be related to the deletion of the 18p material from the r(18) chromosome.

Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland.

Germline mutations in the BRCA1 and BRCA2 genes account for the majority of high-risk breast/ovarian cancer families, depending on the population studied. Previously, BRCA1 mutations were described in women from Western Poland. To further characterize the spectrum of BRCA1 mutations and the impact of BRCA2 mutations in Poland, we have analyzed 25 high-risk breast and/or ovarian cancer families from North-Eastern Poland for mutations in all coding exons of the BRCA1 and BRCA2 genes, using combined heteroduplex analysis/SSCP followed by direct DNA sequence analysis. Out of 25 probands a total of five (20%) carried three recurrent BRCA1 mutations (300T>G, 3819del5, 5382insC). The 300T>G mutation accounted for 60% (3/5) of BRCA1 mutations and allelotyping suggested a common founder of this mutation. No unique mutations were found. In addition, we identified three BRCA2 (12%) mutations, one recurrent 4075delGT, and two novel frameshift mutations, 7327ins/dupl19 and 9068delA. We conclude that 30% of high-risk families from North-Eastern Poland may be due to recurrent BRCA1 and unique BRCA2 mutations. Intriguingly, the BRCA1 mutation spectrum seems to be different within subregions of Poland.

[Treatment of essential thrombocythemia--personal experience]. / Leczenie nadplytkowosci samoistnej--doswiadczenia wlasne.

The present paper summarizes 13-years our center's experience in the treatment of essential thrombocythemia (ET). We analyzed a group of 36 patients treated with busulphan (Bu), 16 with hydroxyurea (HU) and 4 with interferon alpha (INF alpha). The results of therapy were assessed using proposed self-defined criteria of ET remission. The remission of ET was achieved in 75% of the patients treated with Bu and 57% treated with HU followed for at least 2 years. In the INF alpha treated group cytoreduction was achieved only in patients in whom initial dose of INF alpha was 6 mln I.U. per day. HU seems to be the drug of choice in younger patients because of possible mutagenic effect of Bu as well as in those, in whom Bu was administered in high total dose. During the cytoreductive or maintenance therapy with HU the blood morphology should be often controlled because of relatively high frequency (40%) of leukopenia. In each case of ET cytogenetic examination is necessary. Ph-positive ET determine the choice of the treatment.

Chromosome aberrations, spontaneous SCE, and growth kinetics in PHA-stimulated lymphocytes of five cases with Sézary syndrome.

Cytogenetic studies of five patients with Sézary syndrome (SS) revealed clonal chromosome aberrations in all cases. In one patient, a del(8)(p21) was the sole abnormality, whereas the remaining cases had karyotypes with multiple chromosome changes. In three SS cases with hypodiploid chromosome numbers, structural rearrangements affecting regions 10q22-24 and 12p11-13, and aberrations leading to loss of material from 17p were found concurrently. Bands 14q11 and 14q32 were involved in structural rearrangements in one case each. Our results and review of 51 published previously SS cases that were analyzed with banding techniques indicate that the chromosomes most frequently involved in structural changes were chromosomes 1 and 2 (in 43% of cases), 6 (in 38%), 17 (in 34%), 14 (in 27%), 11 (in 25%), 13 (in 21%), and 9 (in 20%). In particular, the breakpoints tended to aggregate at 1p11, 1p36, 2p11-24, 6q, 9q, 11q, 13q11-14, 14q11, 14q32, and in the pericentric region of chromosome 17. The most common numerical change was loss of chromosome 10, detected in 32% of SS cases. In our studies of three SS cases, sister chromatid exchange frequencies were significantly higher in comparison to the normal control. Cell cycle kinetics analysis revealed that the cell cycle time in the malignant cells was significantly longer than in lymphocytes of normal individuals.