BACKGROUND: Analysis of the major breast cancer (BC) predisposition genes BRCA1 and BRCA2 enables identification of high-risk individuals. Specialized programs enrolling the carriers of BRCA1/2 mutations facilitate an improvement in prevention and early diagnostics in asymptomatic individuals and rationalize the selection of individualized treatment in case of a BC onset. However, the carriers of mutations in the major predisposition genes represent only approximately 25% of cases among high-risk BC patients. Numerous candidate predisposing genes for breast and other cancers have recently been identified. The risk of cancer development associated with alterations in these genes is lower, and there is a considerable population variability in different regions worldwide. AIM: We have performed mutation analyses of moderate-risk cancer susceptibility genes to evaluate their clinical importance for genetic counseling in high-risk patients suffering from breast and other cancers in the Czech population. RESULTS: Czech oncological patients were analysed for mutation in ATM, CHEK2, NBS1 (NBN) and PALB2 genes. The majority of analyzed individuals represent the population of high-risk BRCA1/2-negative BC patients. CONCLUSIONS: Based on results of this study, we recommend an analysis of recurrent truncating mutations in the CHEK2 gene (the c.1100delC mutation and a large deletion affecting exons 9-10) in BRCA1/2-negative patients from high-risk BC families. A clinical assessment of missense variants in CHEK2 is not suitable. A routine mutation analysis of the ATM and NBS1 (NBN) genes is not recommended in BC patients due to the low frequency of alterations in these genes in the Czech Republic. An identification of truncating mutations in the PALB2 gene is important in BRCA1/2-negative BC patients from families with a strong history of BC (HBC families). The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech HBC families.

• MeSH
• ATM protein MeSH
• checkpoint kinasa 2 MeSH
• DNA vazebné proteiny genetika   MeSH
• genetická predispozice k nemoci * MeSH
• genetické testování * MeSH
• geny BRCA1 MeSH
• geny BRCA2 MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory prsu diagnóza   genetika   MeSH
• protein FANCN MeSH
• protein-serin-threoninkinasy genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• tumor supresorové geny MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• checkpoint kinasa 2 MeSH
• CHEK2 protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• PALB2 protein, human MeSH Prohlížeč
• protein FANCN MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH

The two major susceptibility genes, BRCA1 and BRCA2, are involved in hereditary breast and ovarian cancer syndrome. Early detection of mutation carriers has crucial clinical importance, as it allows identification of women who may benefit from intensive clinical follow-up or prophylactic surgery. Generally accepted inclusion criteria for BRCA1/2 mutation testing are based either upon family history of breast or ovarian cancer or young age at cancer diagnosis. In order to analyze the impact of BRCA1/2 mutations on breast cancer development in the Czech population and to confront the clinical and histopathological data of mutation carriers with current criteria for mutation testing we examined the frequency of mutations in unselected breast cancer cases. Mutational analysis of BRCA1/2 genes performed in 679 unselected female breast cancer patients included all recurrent deleterious alterations previously identified in the Prague area and truncating mutations in the whole exon 11 of BRCA1. Within analyzed gene sequences more than 80% of mutations were identified previously in high-risk patients. A total of 16 breast cancer patients (2.4%) carried a mutation. BRCA1 mutations were identified in 14 (2.1%) whereas BRCA2 in 2 (0.3%) women. Family history of ovarian cancer was a strong predictor of a BRCA1/2 mutation (OR = 8.3; p = 0.01), however, family history of breast cancer was not indicative of carrier status. A significant association between medullary breast cancer and mutation status was observed. Current criteria for BRCA1/2 mutation testing would distinguish only 6 out of 16 (37.5%) carriers identified in our study. Ten breast cancer patients with confirmed BRCA1/2 germ-line mutation exhibited no clinical characteristics that would predict their carrier status. Therefore, we believe that the testing for BRCA1/2 mutations in the Czech Republic may not be restricted only to high-risk patients. Our results indicate that analysis of locally prevalent BRCA1/2 mutations in all breast cancer patients might extend substantially the percentage of identified mutation carriers.

• MeSH
• detekce genetických nosičů * MeSH
• dospělí MeSH
• geny BRCA1 * MeSH
• geny BRCA2 * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• nádory prsu genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUNDS: Carriers of hereditary mutations in cancer susceptibility genes represent a limited but high-risk population characterized by a high probability of cancer development, frequently with its manifestation in early age and with a 50% chance of pathogenic allele inheritance by offspring. In case of monogenic disorders, preimplantation genetic diagnosis (PGD) could be used for characterization of the DNA region affected by pathogenic mutation in the early stages of an embryo created by in vitro fertilization (IVF). Therefore, the transfer of unaffected embryos could be performed based on the results of PGD genotyping, enabling the development of offspring not carrying the pathogenic alteration. AIM: Here we present the consensus of the collaborative group of the Society for Medical Genetics, the Czech Society for Oncology and other professionals for use of PGD in the Czech Republic for carriers of mutations in cancer susceptibility genes. We address the conditions, prerequisites, and limits of practical application of this method. We also point out specific issues of ovarian hyperstimulation in carriers of mutations in BRCA1, BRCA2, and p53, anticipating the increased risk of hormonally dependent breast and ovarian cancers development. CONCLUSIONS: We assume that a narrow but non-negligible subgroup of cancer susceptibility gene mutation carriers may benefit from PGD.They are mainly individuals deciding to undergo IVF and PGD recruited from mutation carriers with extreme concerns about transmitting the mutation to their children. The PGD in these individuals should be managed by a closely cooperating multidisciplinary team of professionals responsible for indication of PGD, giving complete information regarding the IVF and PGD procedures including their limits, evaluating individual risks and performing instrumental and laboratory procedures with respect to up-to-date good laboratory and clinical practice.

• MeSH
• fertilizace in vitro MeSH
• genetická predispozice k nemoci MeSH
• heterozygot * MeSH
• lidé MeSH
• nádory genetika   prevence a kontrola   MeSH
• preimplantační diagnóza * metody   MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

OBJECTIVE: To analyze loss of heterozygosity (LOH), loss of expression and somatic mutations of BRCA1, BRCA2 and p53 genes in sporadic epithelial ovarian cancer samples. DESIGN: Original paper. SETTING: Oncogynecologic center, Clinic of Obstetrics and gynecology, First Faculty of Medicine, Charles University in Prague and General Teaching Hospital, Prague. MATERIAL AND METHODS: We used genomic DNA and total RNA from peripheral blood and fresh frozen tumor as a template for LOH, loss-of-expression and mutation analyses. RESULTS: LOH in at least one region was found in 60% of tumors. Majority of these alterations occurred not solely, but in conjunction with other region deletions. CONCLUSION: Our study confirms high frequency of somatic alteration of BRCA1, BRCA2 and p53 genes in sporadic epithelial ovarian cancer.

• MeSH
• exprese genu MeSH
• geny p53 genetika   MeSH
• karcinom genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádory vaječníků genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• umlčování genů * MeSH
• ztráta heterozygozity MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protein BRCA1 MeSH
• protein BRCA2 MeSH

We aimed at determining whether any association exists between six single nucleotide polymorphisms in breast cancer associated gene (BRCA1) and the risk of breast cancer. We constructed haplotypes and analyzed their importance as well. Clinico-pathological characteristics of breast cancer patients were included in the study to evaluate the prognostic impact of BRCA1 polymorphisms and haplotypes. Polymerase chain reaction-restriction fragment length polymorphism-based genotyping assays were used to determine the frequency of polymorphisms in codons 356, 871, 1038, 1183, 1436, and 1613 of BRCA1 in a group of 306 incident breast cancer patients and 313 unaffected controls of Czech origin. Statistical analyses revealed that the BRCA1 Arg356 allele may play a protective role in breast cancer (age-adjusted OR = 0.61, CI = 0.39-0.94, p = 0.026). We also observed a significant correlation between polymorphism Gln356Arg and stage (p = 0.026) in premenopausal cases suggesting that carriers of the wild Gln356Gln allele are at significantly higher risk of advanced disease. The most common haplotypes of BRCA1 did not play a significant role in breast cancer either as risk factors or as prognostic factors. The study on rare BRCA1 haplotypes however should be repeated using larger groups. In conclusion, the BRCA1-Gln356 allele presents risk factor in the onset and progression of breast cancer in Czech population and its use as a possible screening tool should be considered.

• MeSH
• dospělí MeSH
• geny BRCA1 * MeSH
• haplotypy MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu genetika   patologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: This article reviews the topic of hereditary ovarian cancer, describes persons at risk of hereditary disposition to cancer and gives instructions for genetic counselling and molecular analysis, including contacts to specialized centres in the Czech Republic. SUBJECT: Review. SETTING: Institute of Biochemistry and Experimental Oncology, Charles University in Prague. METHODS: Hereditary ovarian cancer occurs in three autosomal dominant syndromes: appropriate hereditary ovarian cancer (HOC), hereditary breast and ovarian cancer (HBOC) and hereditary non-poliposis colorectal cancer (HNPCC). Physician in practice or specialist at the clinic should focus interest on patients form families with frequent occurrence of breast and/or ovarian cancer, patients with early onset disease or tumour duplicity (breast and ovarian cancer). Hereditary disposition to ovarian (and breast) cancer could be assessed by molecular genetic analysis of two main susceptibility genes BRCA1 and BRCA2, or other genes in families with diverse tumours. Molecular genetic analysis should be in any cases indicated by experienced clinical genetic. In the Czech Republic, the consensus of genetic and clinical care of risk patients was published and specialized centres for families with hereditary predisposition were settled in Prague and Brno. CONCLUSION: Persons with hereditary susceptibility to cancer constitute noted group where painstaking dispensarisation and preventive care may prevent malignancy or detect it in the early stage.

• MeSH
• dědičné nádorové syndromy genetika   MeSH
• geny BRCA1 MeSH
• geny BRCA2 MeSH
• lidé MeSH
• mutace MeSH
• nádory prsu genetika   MeSH
• nádory vaječníků genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH

Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5-10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian cancer risk group to characterize the spectrum of its mutations in the Czech Republic. Five overlapping fragments amplified on both genomic DNA and cDNA were used to screen for the whole protein-coding sequence of the BRCA1 gene. These fragments were analysed by the protein truncation test (PTT) and direct sequencing. Three inactivating mutations were identified in the group of 30 Czech ovarian cancer patients: the 5382insC mutation in two unrelated patients and a deletion of exons 21 and 22 in another patient. In addition, we have found an alternatively spliced product lacking exon 5 in two other unrelated patients. The 5382insC is the most frequent alteration of the BRCA1 gene in Central and Eastern Europe. The deletion of exons 21 and 22 affects the BRCT functional domain of the BRCA1 protein. Although large genomic rearragements are known to be relatively frequent in Western European populations, no analyses have been performed in our region yet.

• MeSH
• dospělí MeSH
• geny BRCA1 * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• nádory prsu genetika   MeSH
• nádory vaječníků genetika   MeSH
• senioři MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Part of breast and ovarian cancer cases develops on the hereditary predisposition, i.e. mutation in one of predisposing genes. Although this proportion is relatively small, 5-10% of all breast and ovarian carcinomas, it represents a group with clearly defined etiologic factor. Predictive analysis of unaffected family members allows to identify individuals at high risk of cancer and to include them into the programme of primary and secondary cancer prevention. Following article presents basic review of the hereditary predisposition to breast and ovarian cancer focusing especially on BRCA1 and BRCA2 genes, which are responsible for almost three-quarters of those hereditary tumours.

• MeSH
• detekce genetických nosičů MeSH
• genetická predispozice k nemoci MeSH
• geny BRCA1 MeSH
• geny BRCA2 MeSH
• lidé MeSH
• nádory prsu genetika   MeSH
• nádory vaječníků genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Microsatellites are tandem repeats of simple polymorphic sequences randomly distributed in non-coding regions of DNA. They can be used in cancer genetics and indirect cancer diagnosis and can help unraveling the genetic basis of tumor formation and progression of cancer. Breast cancer is a complex disease in which numerous genetic alterations occur. The knowledge of specific genetic changes and their biological consequences is critical to an understanding of breast cancer tumorigenesis, screening and treatment of patients. Microsatellites can undergo two events during tumor progression. Loss of heterozygosity indicates absence of one allele in a given locus, which is associated with the loss of a corresponding genes. Microsatellite instability reflects replication errors induced by defective function of mismatch repair genes and is demonstrated with the appearance of novel, noninherited alleles in tumor cells and represents a specific pathway of tumor development. Both events serve as prognostic markers, which can be correlated with clinicopathological features and can help exploring breast cancer formation.

• MeSH
• genetické markery MeSH
• lidé MeSH
• mikrosatelitní repetice * MeSH
• nádory prsu diagnóza   genetika   MeSH
• ztráta heterozygozity MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• genetické markery MeSH

Heterozygous carriers of germ-line mutations in the BRCA1 gene are at high risk for the development of breast and ovarian cancer. Inactivating mutations have been identified in the whole coding region of the gene, however, repeatedly occuring mutations can explain a large proportion of gene alterations detected in certain ethnic groups. In Czech patients, the 5382insC and 185delAG mutations may account for approximately 50% of all BRCA1 abnormalities (unpublished data). In the present study, a rapid and simple method to identify these short insertions and deletions that alter the size of the polymerase chain reaction (PCR) product is described. The analysis involves the separation of fragments amplified with primers that flank altered sites in the BRCA1 gene on non-denaturing polyacrylamide gels containing Spreadex Polymer NAB. The increased resolving power of Spreadex gels enables full separation of two DNA fragments that differ by 1-bp on gels that are 5 cm long. The method gave interpretable results with the genetic material obtained from all tested mutation carriers and control persons. Defective alleles were also detected in DNA samples from carriers of the 1135delA mutation in BRCA1 and the 4206ins4 mutation in BRCA2. These results suggest that electrophoresis on Spreadex gels can be used universally for detection of the most frequent frameshift mutations in BRCA genes. The method is suitable even for rapid screening of frequent germ-line mutations in BRCA genes in breast and ovarian cancer patients not selected for family history of cancer or age at diagnosis.

• MeSH
• akrylové pryskyřice * MeSH
• DNA nádorová analýza   MeSH
• DNA primery chemie   MeSH
• geny BRCA1 * MeSH
• lidé MeSH
• mutační analýza DNA metody   MeSH
• nádory prsu diagnóza   genetika   MeSH
• nádory vaječníků diagnóza   genetika   MeSH
• plošný screening metody   MeSH
• polymerázová řetězová reakce MeSH
• transportní proteiny genetika   metabolismus   MeSH
• ubikvitinligasy MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylové pryskyřice * MeSH
• BRAP protein, human MeSH Prohlížeč
• DNA nádorová MeSH
• DNA primery MeSH
• polyacrylamide gels MeSH Prohlížeč
• transportní proteiny MeSH
• ubikvitinligasy MeSH