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The prognosis of patients with BRCA1-related breast carcinomas is inferior to the patients without BRCA1 mutation, but most of these tumors have a so-called triple negative phenotype characterized by increased chemosensitivity. Information regarding the chemosensitivity of BRCA1-related breast carcinomas is limited. We present a case of a mother and daughter with hereditary breast carcinoma treated with primary chemotherapy using the dose-dense combination of doxorubicin and cyclophosphamide and sequential weekly paclitaxel administration. Pathological complete response was observed in both patients. Subsequent genetic analysis revealed the same BRCA1 mutation with exon 5-14 deletion in both women. The present experience as well as other reports indicate increased sensitivity of BRCA1-related breast carcinoma to primary chemotherapy.

The PML protein is concentrated in the PML nuclear bodies. Downregulation of the PML protein has been described in various types of cancer and is in accordance with the fact that dysqualification of tumor suppressive functions of the PML protein might promote cancer development. Various differences have been described between sporadic breast cancer and that associated with BRCA1 and BRCA2 gene mutations. Expression of the PML protein has not been studied yet. The aim of this study was to determine if there is any difference in PML protein expression in breast cancer of BRCA1 and BRCA2 gene mutation carriers compared to sporadic breast cancer and if the PML protein can be used as a prognostic marker. There were 47 breast cancer samples included, 14 and 10 from BRCA1 and BRCA2 germline mutation carriers, respectively, and 23 from patients without a BRCA1/BRCA2 germline mutation. Immunofluorescence staining was used. Downregulation of PML protein expression was found in 2 of 14 (14%), 3 of 10 (30%) and 15 of 47 (31%) cases of breast cancer samples from BRCA1, BRCA2 and no BRCA1/BRCA2 mutation carriers, respectively (p(BRCA1) = 0.019; p(BRCA2) = 0.111). There was no correlation between PML protein expression and age, histological types, estrogen and progesterone receptor, c-erbB-2 and PCNA expression, TNM classification, disease-free and overall survival. In conclusion, the PML protein is downregulated in approximately 30% of breast cancers cases. Downregulation of PML protein expression was significantly less frequent in BRCA1 mutation carriers compared to sporadic cases. No correlation was found between PML protein expression and any of the other clinical and laboratory characteristics.

The PML (promyelocytic leukemia) protein is concentrated in the PML nuclear bodies. In human cell lines and tumors maintaining their telomeres by alternative lengthening (ALT), the PML protein is colocalized with TRF2 and several other proteins in the so called ALT-associated PML bodies. The aim of this study was to determine if there is any difference in PML protein expression between tumors with stable microsatellites (MSS) and those with high-frequency microsatellite instability (MSI-H), if PML protein expression might be a prognostic factor and if MSI-H tumors more frequently use alternative lengthening of telomeres measured by the presence of ALT-associated PML bodies. Eighty colorectal cancer samples (32 MSI-H and 48 MSS) and 8 human tumor cell lines (Saos-2, U2OS, DU145, LNCaP, U87, HeLa, MCF7 and T98G) were included into the study. Double-colour immunofluorescence staining was used. Downregulation of PML protein expression was found in 7 of 32 (22%) MSI-H and 11 of 48 (23%) MSS tumors (p=0.520). There was no correlation between PML expression and age, histological typing, localization of the tumor in colon, TNM classification, disease-free and overall survival. The Saos-2 and U2OS (ALT using cell lines) and the MCF7 (active telomerase) cell line were characterized by the presence of ALT-associated PML bodies; no such bodies were detected in the DU145, LNCaP, U87, HeLa and T98G cell lines (active telomerase); accumulation of TRF2 was absent or much weaker in these cell lines compared to Saos-2 or U2OS. Accumulation of the TRF2 protein was detected in 16 of 80 (20%) tumors and PML and TRF2 colocalization in 2 MSI-H tumors (6%). In conclusion, the PML protein was downregulated in approximately 20% of tumors; there was no difference between MSS and MSI-H tumors. PML protein expression does not seem to be a prognostic factor.

Defects in DNA mismatch repair system are involved in carcinogenesis of sporadic and inherited human cancers. We assessed the feasibility of using immunohistochemistry to detect tumors with DNA mismatch repair deficiency. We analyzed 81 samples (74 colon cancers (CC), 1 colon dysplasia and 6 extracolonic cancers) for hMLH1 and hMSH2 protein expression, microsatellite instability (MSI) and/or mutational analysis. A meta-analysis of the published data on immunohistochemistry of hMLH1/hMSH2 proteins was performed. Sensitivity and specificity of the method was calculated. Twenty four of 29 tumors from hMLH1/hMSH2 mutation carriers and 10 of 13 sporadic high frequency MSI tumors lost one of the proteins. None of the 42 tumors with stable microsatellites or low frequency MSI lost the proteins. Based on literature review of 49 publications on colorectal cancer, hMLH1 immunohistochemistry was able to detect 136 of 154 tumors from hMLH1 germline mutation carriers (the sensitivity of 88.3% [95%CI, 85.8-90.8%]), hMSH2 immunohistochemistry detected 99 of 109 tumors from hMSH2 mutation carriers (the sensitivity of 90.8% [95%CI, 88.5-93.1%]), and hMLH1/hMSH2 immunohistochemistry identified 1262 of 1382 tumors with high-frequency microsatellite instability not correlated with mutational analysis (the sensitivity of 91.3% [95%CI, 90.4-92.2%]). The specificity of the method was 99.4% (95%CI, 99.2-99.6%). In conclusion, immunohistochemistry of hMLH1 and hMSH2 proteins is a useful method to predict the presence of mismatch repair deficiency, although its sensitivity is lower than that of MSI analysis.

Background: About 5-10% of breast and ovarian cancer can be of hereditary origin. Germline mutations in BRCA1 or BRCA2 and probably other yet unknown genes may cause predisposition to these cancers., Methods and Results: Molecular genetic testing of BRCA1 and BRCA2 genes in 21 high-risk breast and breast/ovarian cancer families was performed in order to find the types and the frequency of mutations in the South Moravian region of the Czech Republic. A germline mutation was found in 12 of 21 tested families (57%), 9 mutations in BRCA1 gene and 3 mutations in BRCA2 gene. In 4 unrelated families the same germline mutation in the BRCA1 gene (5382insC) was identified. In 12 families diagnosed with breast cancer only syndrome 3 families harbouring BRCA1 mutations and 3 families harbouring BRCA2 mutations were found. In 9 families with breast-ovarian cancer syndrome 6 families carrying BRCA1 mutations were detected., Conclusion: Molecular genetic testing of BRCA1 and BRCA2 genes in high-risk women with breast/ovarian cancer is effective in determining genetic predisposition to cancer. Spectrum of mutations found in both genes is variable and further investigation is needed for estimation of more frequent or "founder" mutations. The genetic counselling and preventive clinical follow-up of gene carriers has to be part of the genetic program.

Immunohistochemical method detecting dystrophin in muscle biopsies was introduced and applied in 121 cases with a large scale of neuromuscular diseases. A monoclonal antibody NCL-DYS 2 (Novocastra) was used for the detection of C-terminal domain of dystrophin. Normal, i.e. sarcolemmal, localization of dystrophin was found in controls, in inactivity atrophy, neurogenic lesions and congenital myopathies. A similar situation except regenerating fibres was found in myositis and progressive muscular dystrophies different from Duchenne (DMD) and Becker (BMD) types, DMD cases showed a complete or nearly complete loss of sarcolemmal reaction product, whereas a partial loss of dystrophin in membrane was found in BMD cases as well as in transmitter females. Fibres splitting during neurogenic and myogenic lesions had dystrophin in newly produced sarcolemmal parts. Sarcolemmal immunoreactivity starting as early as in the 10th-12th week of gestation was found in human fetuses.

In an attempt to elaborate a method for screening heterozygous carriers of inborn adrenal hyperplasia caused by insufficiency of steroid 21-hydroxylase, the authors examined in 24 obligatory heterozygotes and in seven controls the concentrations of four steroids. Cortisol (F), 11 beta-hydroxyandrostendione (11-OH), 17 alpha-hydroxyprogesterone (17-OH) and androstendione (A) were estimated by the RIA method using non-commercial antisera. In the examined subjects an abbreviated ACTH test was made and the mentioned parameters were assessed at times 0, 30 and 60 minutes. The results (nmol/l) were expressed by the relationship R = F.11-OH/17-OH.A for all investigated time intervals. The coefficient R60 or difference of coefficients delta R = R60-R0 differed significantly and overlapped to a minimum extent in the group of heterozygotes and controls. The authors assume that the suggested method for the detection of carriership of 21-hydroxylase insufficiency could be used in genetic counselling.