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Background: The PALB2 (FANCN) gene was identified as a component of endogenous BRCA2 complex that encodes a DNA repair protein participating along with BRCA1 and BRCA 2 proteins in DNA double-strand break repair. Hereditary PALB2 mutations are associated with an increased risk of breast and pancreatic cancers in heterozygotes. Breast cancer risk for PALB2 mutation carriers has recently been estimated at 33-58% depending on family history of breast cancer; pancreatic cancer risk in carriers of PALB2 mutations has not been precisely quantified, yet., Materials and Results: Results of a study identifying PALB2 mutations in high-risk, BRCA1/2-negative, breast and/or ovarian cancer patients in the Czech Republic indicate that the frequency of hereditary PALB2 mutations in our population is quite high. Interestingly, almost 20% of all recognized mutations comprised large genomic rearrangements. The highest proportion of PALB2 mutations (comparable with the number of mutations reported for BRCA2) was found in a subgroup of hereditary breast cancer patients (5.5%). Frequency of mutations in an independent group of Czech unselected pancreatic cancer patients was approximately 1.3%., Conclusion: Considering the frequency of pathogenic, hereditary PALB2 mutations in our population, their phenotypic similarity to BRCA2, and expected risk of breast cancer associated with PALB2 mutations, its screen-ing (including large genomic rearrangements) should be encouraged in patients from hereditary breast cancer families. The follow-up of pathogenic PALB2 mutation carriers should be similar to that in BRCA2 mutation carriers, enabling early diagnosis, prevention, and possible targeted therapy. Preventive surgical interventions for the carriers could be considered in case of strong family cancer history and evident segregation of a pathogenic mutation with a tumor phenotype. Additional analysis of various cancer patient populations and further meta-analyses will be necessary for accurate assessment of PALB2 gene penetrance and its significance for the risk of pancreatic and other cancers.

Background: Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested., Methods: For this retrospective study we used the TruSight cancer panel (Illumina)--NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes. All pathogenic and potentially pathogenic mutations detected by NGS technology have been confirmed by Sanger sequencing., Results: There were several deleterious (frame-shift/nonsense) mutations detected in ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4 genes. Various pathogenic or potentially pathogenic (missense, predicted splice site, in-frame insertion/deletion) mutations were detected in ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. These mutations affect highly conserved protein domains and affect their function as proved by the available functional assays. They were confirmed to be pathogenic as an "Parent No2 " in serious recessive diseases such as Ataxia telangiectasia or Fanconi anemia. The clinical significance of the majority of detected missense variants still remains to be identified., Conclusion: Moderate or low penetrance variants are of limited clinical importance. Panel genetic testing in high-risk individuals with cancer provides important information concerning the cause of the investigated cancer, and may assist in the risk assesment and optimal management of the cancer, as well as in further preventive care.

Fanconi anemia is a rare autosomal recessive disorder, clinically and genetically heterogeneous, characterized by typical clinical features, such as short stature, microcephaly, skeletal abnormalities, abnormal skin pigmentations, developmental delay and congenital heart, kidney anomalies etc. Pancytopenia leading to bone marrow failure occurs in the first decade. Patients with Fanconi anemia have a high risk of hematologic malignancies and solid tumors. The diagnosis of Fanconi anemia is based on cytogenetic testing for increased rates of spontaneous chromosomal breakage and increased sensitivity to diepoxybutane or mitomycin C. Fanconi anemia is a heterogeneous disorder, at least 15 complementation groups are described, and 15 genes in which mutations are responsible for all of the 15 Fanconi anemia complementation groups have been identified. Unlike other Fanconi anemia complementation groups, for complementation group D1 (FANCD1), the bone marrow failure is not a typical feature, but early-onset leukemia and specific solid tumors, most often medulloblastoma and Wilms tumor, are typical for this complementation group.

Genetic testing for hereditary breast and ovarian cancer syndrome is indicated by a genetic counselor on the basis of personal and family history evaluation, with regards to consensual criteria, reflecting the current knowledge. The latest recommendation accepted by Czech Oncology Society and Society of Medical Genetics was published in the supplement 22 to the Journal of Clinical Oncology in 2009. Since the availability of PARP inhibitors for treatment of ovarian cancer in BRCA1/ 2 mutation carriers, an update of these guidelines is urgently needed. Another reason is a higher incidence of other malignancies in high-risk families, such as prostate or pancreatic cancer. The goal is to refine the detection of mutations in selected families, to improve preventive care and collect data necessary for targeted cancer treatment.

Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.

Unlabelled: It is presumed that bilateral mastectomy is so far the most efficient way how to prevent development of breast carcinoma among BRCA positive patients. This mutilating intervention might be unacceptable for cosmetic reasons for most women. The purpose of this study was to determine the influence of prophylactic mastectomy on the quality of life of BRCA positive patients by comparing results of psychodiagnostic questionnaire methods before surgical intervention and after it. Our data set consisted of 25 BRCA positive healthy women and 19 BRCA positive women in remission. All these patients underwent a reconstructive surgical intervention after mastectomy. Age of patients was 38-55 years. The following questionnaires were used: Life Satisfaction Questionnaire by J. Fahrenberg, M. Myrtek and E. Brähler, Clinical analysis questionnaire by S. E. Kruge and R. B. Cattel, Impact of Event Scale - Revised by D. S. Weiss and C. R. Marmar., Results: Women in remission showed most significant decrease in Financial position category and minor decrease in Work and Employment category and Friends, Acquaintances and Relatives category. Improvement of quality of life was recorded especially in category of Health, Sexuality, Own person, Partnership and in Relationship with own children and there was also a significant improvement to overall life satisfaction. Among healthy patients, there was a significant improvement in category of Health and Own person. Most significant decrease was in dimension of Financial position and Work and employment. Prophylactic mastectomy with reconstruction might be the way of prevention of breast carcinoma because from psychological point of view there is the unambiguously significant fact that there was improvement of perception of own health and own person in both groups of women. These are the quality of life aspects that are considered to be basal and long term stabilizing from the perspective of dynamics of own self and they also systematically influence other aspects of quality of life which are derived from them.

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.

Preventive oncology clinic of MMCI provides complex preventive care for women with high hereditary risk of breast and ovarian cancer due to germline mutations in BRCA1 and BRCA2 genes. Clinical follow-up is also provided to women with mutations in other genes causing a higher risk of different tumors, and also to women with increased lifetime empirical risk of breast cancer due to positive family history. Our clinic was established in 2000 and takes care for about 700 women. The goal of the clinic is to extend the life expectancy of these women to the level of the regular population. The risk of breast cancer can be reduced by prophylactic surgeries. Prophylactic mastectomy and oophorectomy are offered to women at a high risk. Other modality in breast cancer risk reduction is a chemoprevention by Tamoxifen. Most women accept only secondary prevention with the goal of the detection of breast cancer in clinical stage I, where the tumor is smaller than 1 cm and the risk of recurrence is less than 10%. The algorithm of prevention care was changed over the time and our diagnostic methods were improved by magnetic resonance imaging of breasts. During the 11 years of clinical follow-up 32 breast cancers in 31 women were detected. High risk women are examined every 6 month by physical examination, breast ultrasound and MRI plus mammography yearly.

Background: Endogenous processes and exogenous agents cause constant DNA damage. DNA double-strand breaks are among the most serious types of damage. They are mainly repaired by homologous recombination, where the BRCA2 protein plays a dominant role. Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance and prophylactic surgery. Apart from clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. Since the influence of these variants on cancer risk is unknown, they represent a major clinical problem., Aims: The aim of this paper is to summarize the current possibilities of predicting pathogenicity of BRCA2 variants. In some cases, genetic methods are able to classify variants with high probability; however, their use is often limited by low frequency of the variants or inaccessibility of samples for mRNA isolation or DNA from family members. Alternatively, functional assays performed in various cellular models may be employed. Multiple functional tests and cellular models are presented and characterized, including their advantages and limitations. A new model of human syngeneic cell lines developed by the authors is presented, in which one BRCA2 allele is deleted and the variant is introduced into the other allele by homologous recombination. This model has the potential to evaluate function of variants without some of the unwanted effects of the other models. Currently, this model is being applied to variants identified in patients with hereditary cancer predisposition in the Masaryk Memorial Cancer Institute., Conclusion: Functional assays in cellular models including a new model of syngeneic cell lines described by the authors have a great potential in evaluating clinical importance of unclassified variants in the BRCA2 gene, especially in cases where genetic tests are not applicable.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome with a high lifetime risk of diffuse gastric cancer and also a high risk of lobular breast carcinoma. Hereditary diffuse gastric cancer (HDGC) is characterized by late presentation and a poor prognosis. The average age of onset of HDGC is 38 years, with a range of 14-69 years. The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women. Many families with HDGC have germline mutations in the E-cadherin (CDH1) gene. We describe indication for genetic testing of germline mutations in CDH1 gene, possibilities of predictive testing, preventive care, prophylactic gastrectomy and preimplantation diagnosis.

Background: Women with BRCA1 gene mutation have 85% risk of breast cancer; the risk for BRCA2 carriers is 45%. The aim of the study was to verify if prophylactic mastectomy with immediate breast reconstruction can prevent breast cancer in BRCA positive patients., Material: There were 100 BRCA positive women in which prophylactic mastectomy with immediate reconstruction, 75 dieps, 25 with implants, performed in period 2000-2011. Group A was composed of healthy, non-affected 41 patients, group B of 59 patients in remission after breast cancer treatment. These groups were compared to group C that consisted of 219 healthy carriers of BRCA1/2, non-operated, from registry of genetic department of the Masaryk Memorial Cancer in Brno, from 2000-2011., Method: Follow-up for oncology status was done in September 2011 for all 3 groups., Results: Average follow-up of 21 months revealed that in group A there was no breast cancer, in group B 4 patients died and 2 had treatment for metastases. In group C, there were 16 new cases of breast cancer., Conclusion: Bilateral prophylactic mastectomy with immediate reconstruction can be an effective way in breast cancer prevention in healthy carriers of BRCA1/2 mutation. In BRCA positive patients treated for breast cancer, the effect of prophylactic mastectomy is unclear. Their survival is more influenced by their previous disease than by a new tumor in the breast.

Introduction and Aim: Male breast cancer (MBC) is a rare disease which represents only about 0.2% of all cancers. The ratio of female to male breast cancer is approximately 100:1. In this study, we review our experience with diagnosis, surgical treatment, and overall management of patients with MBC., Methods: Overall, 5384 breast cancer patients underwent surgery in Masaryk Memorial Cancer Institute, Brno, Czech Republic during the period of 2001 to 2009. Among these, seventeen were men. In these patients, data on incidence, clinical symptoms, diagnostic procedures, types of surgical resection, histopathology, adjuvant systematic therapy, genetic investigation and therapeutic results were retrospectively reviewed from their medical records., Results: None of the patients have distant metastases at the time of surgery. In sixteen cases an invasive cancer was histopathologically diagnosed, one patient had ductal carcinoma in situ (DCIS). Eight patients exhibited locally advanced stage of the disease (IIIB). All patients were primarily treated surgically; in no case neoadjuvant therapy was recommended. From the five patients operated primarily elsewhere, four underwent completion of modified radical mastectomy (RAME) at our institution and one patient underwent subcutaneous (nipple-sparing) mastectomy without the surgery on lymph nodes. Twelve patients were primarily diagnosed and operated at our institution. Ten of these were scheduled for RAME, one patient was recommended total mastectomy with sentinel lymph node biopsy, and one patient underwent total mastectomy without surgery on regional lymph nodes. Adjuvant therapy overall comprised radiotherapy, chemotherapy, hormonal therapy, and biological therapy. Investigation of BRCA genes was suggested in nine patients, but the results of only four of them are available to date. Two patients exhibited a mutation in BRCA genes. One mutation is explicitly pathogenic; another case represents variation with unknown clinical effect. Twelve patients of the cohort are in complete remission, two are alive with distant metastases and three died (two on cancer, one on cardiovascular disease)., Conclusion: Our study should point out a rare form of mammary tumors--male breast cancer. There are some particular differences between male and female breast cancer though the overall clinical management of both is generally similar. There is a necessity of appropriate health education to prevent late diagnosis of breast cancer in men. Genetic testing should be recommended to every male patient with this disease.

Genetic testing of cancer syndromes is based on the existing knowledge of monogenic causes of oncologic diseases. In cases of high-risk genes, the findings concerning the carrier status of pathogenic mutation can be of clinical use in the prediction of risks and for preventive care. In non-carriers in families with mutation in the high-risk gene, the risk of cancer diseases may not be the same as the population risk and some preventive follow-up is recommended. The clinical use of genes with mild or moderate risk of cancer is problematic and could lead to distorted conclusions about the actual cause of the familial form of the disease. Predictive testing in genes with moderate risk of cancer (2-3 times) is not offered, or the non-carriers are followed in the same way as carriers. The use of genes with mild risk is not recommended in clinical practice. Molecular genetic testing also has its limitations and its quality depends on the methods and technology used and the existing knowledge of the significance of mutations. In some variants it is not clear yet whether they are just insignificant polymorphisms or pathogenic mutations. The interpretation of test results in the context of the whole family history is important.

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.