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The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society (SLG ČLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Male breast cancer (mBC) is a rare cancer diagnosis that constitutes less than 1 % of all breast cancer cases globally. Genetic factors play an important role in the mBC risk. Germline pathogenic variants (PVs) in cancer predisposition genes could be identified in about 15 % of cases. We performed germline genetic testing in 248 Czech mBC patients and 3,626 non-cancer male controls using next-generation sequencing by the CZECANCA panel (226 genes). We identified 46/248 (18.5 %) carriers of PVs in the established mBC predisposition genes, primarily in BRCA2 (N = 34), less frequently in BRCA1 (N = 7) and PALB2 (N = 5). The presence of a PV in these genes significantly increased the mBC risk (OR 44.04; 5.82; and 8.26, respectively). Additionally, we identified 16 carriers of PVs in candidate mBC genes, but only PVs in CHEK2 were significantly associated with increased mBC risk (OR = 4.98). The significance of 26 germline alterations in 23/192 additionally analysed genes remained uncertain. The carriers of PVs in BRCA1 and CHEK2 were significantly younger (55.8 and 52.6 years, respectively) than non-carriers (64.8 years), and all carriers of PVs in the established genes had more frequently grade G3 tumours and positive family cancer history. Our study underscores the critical role of BRCA2 in mBC predisposition while also highlighting the potential contributions of additional genes that warrant further investigation. Moreover, it supports and justifies universal genetic testing for all mBC patients to generally improve early cancer detection and tailored treatment.

The guidelines for clinical practice for carriers of pathogenic variants in clinically relevant genes predisposing to Lynch syndrome and colorectal cancer define the steps of primary and secondary prevention that should be provided to the individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society, in cooperation with representatives of oncology, oncogynecology, and gastroenterology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Background: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC., Methods: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided., Results: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively)., Conclusions: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers., (© The Author(s) 2023. Published by Oxford University Press.)

Ovarian cancer is one of the most common gynecologic cancers with the highest mortality rate over a long period. Genetic predisposition to ovarian cancer is unusually high. In the Czech Republic, causal mutation in any ovarian cancer predisposition gene is identified in approximately 30% of the ovarian cancer patients. Therefore, according to the current guidelines, all ovarian cancer patients should be provided with genetic testing. The BRCA1 and BRCA2 are the two major ovarian cancer predisposition genes. Nevertheless, mutations in other predisposition genes, including RAD51C and RAD51D, are associated with high ovarian cancer risk. Mutations in RAD51C and RAD51D are found in 1% of ovarian cancer patients in each respective gene. Currently, identification of germline mutation in RAD51C and RAD51D is primarily of preventive importance but it potentially could make a prognostic difference. The aim of this review is to summarize the recent RAD51C and RAD51D knowledge, including the biological function, cancer risks associated with germline mutations, and recommendations for mutation carriers.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis., Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC., Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs., Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association., Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association., (Published by Oxford University Press on behalf of the American Society for Nutrition 2021.)

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.

The emergence of next-generation sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations, such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analysing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub platform: https://github.com/IARCbioinfo/needlestack., (© World Health Organization and the authors, 2020. All rights reserved. The World Health Organization and the authors have granted the Publisher permission for the reproduction of this article.)

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs., (© 2019 Wiley Periodicals, Inc.)

Background: Ovarian cancer is a disease with high mortality. Approximately 1,000 women are diagnosed with ovarian cancer in the Czech Republic annually. Women harboring a mutation in cancer-predisposing genes face an increased risk of tumor development. Mutations in BRCA1, BRCA2, BRIP1, and Lynch syndrome genes (RAD51C, RAD51D, and STK11) are associated with a high risk of ovarian cancer, and mutations in ATM, CHEK2, NBN, PALB2, and BARD1 appear to increase the risk. Our aim was to examine the frequency of mutations in cancer-predisposing genes in the Czech Republic., Materials and Methods: We analyzed 1,057 individuals including ovarian cancer patients and 617 non-cancer controls using CZECANCA panel next-generation sequencing on the Illumina platform. Pathogenic mutations in high-risk genes, including CNVs, were detected in 30.6% of patients. The mutation frequency reached 25.0% and 18.2% in subgroups of unselected ovarian cancer patients and patients with a negative family cancer history, respectively. The most frequently mutated genes were BRCA1 and BRCA2. The overall frequency of mutations in non-BRCA genes was comparable to that in BRCA2. The mutation frequency in ovarian cancer patients aged &gt;70 years was three times higher than that in patients diagnosed before the age of 30., Conclusion: Ovarian cancer is a heterogeneous disease with a high proportion of hereditary cases. The lack of efficient screening for early diagnosis emphasizes the importance of identifying carriers of mutations in ovarian cancer-predisposing genes; this is because proper follow-up and prevention strategies can reduce overall ovarian cancer-related mortality. This work was supported by grants AZV 15-27695A, SVV2019/260367, PROGRES Q28/LF1. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 7. 3. 2019 Accepted: 24. 4. 2019.

Background: BAP1 syndrome is an autosomal dominant hereditary cancer syndrome associated with increased risk of malignant mesothelioma; uveal and cutaneous melanoma; kidney cancer; lung adenocarcinoma; meningioma; basaliomas; and breast, ovarian, and prostate tumors. The BAP1 gene (BRCA1-associated protein 1) is a tumor suppressor gene involved in DNA repair via homologous recombination. BAP1 regulates the cell cycle, differentiation, DNA damage responses, and cell proliferation through deubiquitination. Somatic mutations in the BAP1 gene are common in many types of tumors., Observation: Two families harboring a germline mutation in the BAP1 gene were diagnosed at Masaryk Memorial Cancer Institute (MMCI). A 27-year-old index female from one family was followed-up for multiple nevi. Her mother and uncle had malignant mesothelioma, and her maternal grandmother had uveal melanoma. The index case tested positive for a BAP1 (NM&#95;004656.2): c.217delG/p.Asp73Metfs*5 frame-shift mutation. The melanoma was removed at the age of 28 and 31. In the second family, an 11-year-old index female had two nevi removed from her head, and a spitzoid-type skin lesion was diagnosed at the age of 11. Her 34-year-old mother had multiple nevi, and a skin lesion of spitzoid-type was removed from the abdomen. Both patients harbored a BAP1 (NM&#95;004656.2): c.123-1G&gt;T acceptor splice site mutation (IARC [International Agency for Research on Cancer] class 4 [probably pathogenic]). Preventive measures for BAP1 syndrome should include known risks for cancer. Tumors occur early and repeatedly. At the MMCI, we recommend physical examination by an oncologist, eyes and skin examination, every 6 months; whole-body magnetic resonance imaging, including the central nervous system, every year (or low-dose computed tomography/chest and abdomen magnetic resonance imaging); annual abdominal ultrasound, breast ultrasound, or mammography; a gynecological ultrasound examination every 6 months; colonoscopy starting at the age of 45; and other suitable surveillances based on family history., Conclusion: BAP1 syndrome is a complex cancer syndrome with a high risk of rare malignant mesothelioma, malignant skin and uveal melanoma, spitzoid-type skin lesions, and other tumors. Detection of this syndrome is essential for the survival of high-risk individuals. Supported by the grant project MH CZ - RVO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 5. 2019 Accepted: 6. 6. 2019.

Background: Hereditary mutations in the CHEK2 gene (which encodes CHK2 kinase) contribute to a moderately increased risk of breast cancer (BC) and other cancers. Large variations in the frequency of CHEK2 mutations and the occurrence of variants of unknown clinical significance (VUS) complicate estimation of cancer risk in carriers of germline CHEK2 mutations., Patients and Methods: We performed mutation analysis of 1,526 high-risk Czech BC patients and 3,360 Czech controls. Functional analysis was performed for identified VUS using a model system based on a human RPE1-CHEK2-KO cell line harboring biallelic inactivation of endogenous CHEK2., Results: The frequency of ten truncating CHEK2 variants differed markedly between BC patients (2.26%) and controls (0.11%; p = 4.1 × 1012). We also found 23 different missense variants in 4.5% patients and in 4.0% of controls. The most common was p.I157T, which was found in patients and controls with the same frequency. Functional analysis identified nine functionally deleterious VUS, another nine functionally neutral VUS, and four intermediate VUS (including p.I157T). We found that carriers of truncating CHEK2 mutations had a high BC risk (OR 8.19; 95% CI 4.11-17.75), and that carriers of functionally deleterious missense variants had a moderate risk (OR 4.06; 95% CI, 1.37-13.39). Carriers of these mutations developed BC at 44.4 and 50.7 years, respectively. Functionally neutral and functionally intermediate missense variants did not increase the BC risk. BC in CHEK2 mutation carriers was frequently ER-positive and of higher grade. Notably, carriers of CHEK2 mutations developed second cancers more frequently than BRCA1/BRCA2/PALB2/p53 or mutation non-carriers., Conclusion: Hereditary CHEK2 mutations contribute to the development of hereditary BC. The associated cancer risk in mutation carriers increases with the number of affected individuals in a family. Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic mutation carriers from the age of 40. Surgical prevention and specific follow-up of other tumors should be considered based on family cancer history. The work was supported by grants from the Czech Health Research Council of the Ministry of Health of the Czech Republic NR 15-28830A, 16-29959A, NV19-03-00279, projects of the PROGRES Q28/LF1, GAUK 762216, SVV2019 / 260367, PRIMUS/17/MED/9, UNCE/MED/016, Progress Q26, LQ1604 NPU II and project AV&#268;R Qualitas. The analysis of a set of unselected controls was made possible by the existence and support of the scientific infrastructure of the National Center for Medical Genomics (LM2015091) and its project aimed at creating a reference database of genetic variants of the Czech Republic (CZ.02.1.01/0.0/0.0/16&#95;013/0001634). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 4. 2019 Accepted: 14. 5. 2019.

Background: Deleterious mutations in the BRCA1 and BRCA2 genes account for a considerable proportion of dominantly inherited breast and ovarian cancer susceptibility. The laboratory interpretation has always been dependent on the information available at the time of the report conclusion. The aim of this study has been to review the results from the BRCA testing at Masaryk Memorial Cancer Institute (MMCI)., Patients and Methods: Patients with suspected hereditary predisposition to breast/ovarian cancer, belonging to 7,400 families, were referred by genetic counsellors for BRCA1 and BRCA2 mutation testing at the MMCI from 1999 to the beginning of 2018. Various methods have been used over 20 years of laboratory practice - starting with the Protein Truncation Test and Heteroduplex Analysis via the High Resolution Melting analysis and Sanger sequencing up to Next Generation Sequencing., Results: BRCA1 and BRCA2 mutation screening resulted in the identification of 1,021 families with a germline high-risk BRCA1 mutation and 497 families carrying a high-risk BRCA2 mutation, representing a mutation detection rate of 20.5%. A broad spectrum of unique mutations classified as pathogenic or likely pathogenic has been detected in both genes - 124 in the BRCA1 and 123 in the BRCA2 gene. Other sequence variants (96 unique variants in the BRCA1 and 126 in the BRCA2 gene) have been revised and classified as benign or likely benign. The other 82 unique variants remain classified as of uncertain significance mainly due to a lack of information for inclusion in other groups. All the results are summarised in the tables, including the reasons for their classification., Conclusion: The clinical classification of rare sequence variants identified in the high-risk breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling. Here we present an overview of BRCA mutation frequencies in our region and the retrospective evaluation and eventually reclassification of previously reported rare variants in light of recent findings.

An inherited predisposition to breast cancer underlies 5-10% of breast tumors. High-risk BRCA1 and BRCA2 genes result in an 85% lifetime risk of breast cancer and a 20-60% lifetime risk of ovarian cancer. Next-generation sequencing or massive parallel sequencing are now established testing methods that enable screening for many genes that predispose to heterogeneous hereditary cancer syndromes (22 genes are required by the health insurance companies). In addition to BRCA1 and BRCA2, inherited mutations in other genes predispose to breast and/or ovarian cancer. High-risk breast cancer genes include TP53, STK11, CDH1, PTEN, PALB2, and NF1, while moderate-risk (2-4 times increased risk) breast cancer genes include ATM, CHEK2, and NBN. Moderate risk is also suggested for Lynch syndrome, MUTYH, BRIP1, RAD51C, RAD51D, BARD1, FANCA, FANCC, FANCM, BLM, WRN genes. In heterozygotes for other recessive syndromes the risk of developing breast cancer is subject to current research. Low-risk genes are (mostly) irrelevant from a clinical perspective. Other genes that increase the risk of ovarian cancer include the genes for Lynch syndrome, the BRIP1, RAD51C and RAD51D genes. Preventive care should be proposed based on assumed cumulative breast cancer risk (see http: //www.mamo.cz): a risk of &gt;20% for BRCA1/2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, and NF1; and a risk of 10-20% for BRIP1, RAD51C, RAD51B, BARD1, FANCA, FANCC, FANCM, NBN, BLM, and WRN. The genetic risk should be assessed by a geneticist and be based on inherited mutations and empirical risk according to family history. Prophylactic mastectomy is considered for high-risk gene carriers but not for moderate-risk gene carriers; however, it may be considered if there is an underlying family history, a risk of parenchyma of the mammary gland, or other risk factors. Ovarian cancer risk increases significantly in carriers of the BRIP1, RAD51C, and RAD51D genes. For prevention of ovarian cancer, prophylactic salpingo-oophorectomy is an important component of preventive care. In ovarian cancer families with no identified risk germline mutation, preventive salpingo-oophorectomy is not routinely recommended but may be considered as the only efficient method of prevention due to the increased empirical risk (4 times) of ovarian cancer in first-degree relatives. Supported by the grant project MH CZ - RVO (MMCI, 00209805), AZV 15-27695A and AZV 16-29959A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 5. 2019 Accepted: 31. 5. 2019.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare variant of familial adenomatous polyposis. It is an autosomal-dominant cancer-predisposition syndrome with massive polyposis of the stomach and a significant risk of gastric adenocarcinoma. Li et al., 2016, described point mutations in the Ying Yang 1 binding site of the APC gene 1B promoter associated with GAPPS syndrome. The first GAPPS syndrome in a Czech family was described in 2016. At Masaryk Memorial Cancer Institute, GAPPS syndrome was diagnosed in eight families using Sanger sequencing. In all families, one mutation in promoter 1B of APC gene NM&#95;001127511: c.-191T&gt;C was detected. This mutation was not found in any patient with multiple colon polyposis without a detected classic mutation in the APC gene. In total, 24 carriers of this mutation in promoter 1B of the APC gene were detected. Out of those 24 carriers, 20 had massive gastric polyposis with more than 100 fundic glandular polyps diagnosed between the age of 22 and 65, 5 had already died of adenocarcinoma of the stomach (at the ages of 29, 40, 59, 60 and 64, respectively) and another woman was treated at the age of 29. Two female carriers do not yet have polyposis of the stomach at the ages of 31 and 65, respectively; one female carrier has incipient polyposis at the age of 58. A male carrier does not have any clinical symptoms, gastroscopy was not indicated because of his age. Prophylactic total gastrectomy with D2 lymphadenectomy has already been performed 6 times at Masaryk Memorial Cancer Institute, in 5 cases without adenocarcinoma at the ages of 27, 34, 44, 51 and 66, respectively; in one female carrier adenocarcinoma of the stomach was detected in a histology specimen. Two prophylactic gastrectomies with D1 lymphadenectomy were performed at University Hospital Brno at the ages of 42 and 50, respectively. In the Czech Republic point mutation c.-191T&gt;C (rs879253783) in the 1B promoter of the APC gene is a frequent cause of gastric polyposis with a high risk of gastric adenocarcinoma, even at a young age. Positively tested individuals are recommended to high-risk oncology clinic. A necessary part of the discussion with the patient is information about a preventive gastrectomy.

About 5-10 % of cancer diseases may be caused by genetic predisposition, in ovarian cancer it could be almost 20 % of cases. The cause is mostly a pathogenic germline mutation in tumor suppressor genes, DNA repair genes, less frequently in oncogenes. So far, we know more than 200 hereditary cancer syndromes. The most frequently tested are hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), quite frequent are also hereditary gastrointestinal polyposes. Genetic counseling and testing are routinely available for patients or their relatives. Testing methods are changing; nowadays we use next generation sequencing methods (massive parallel sequencing) with testing of panels of high-risk genes. If the mutation is discovered, we may offer the testing to relatives. Genetic testing is indicated by medical geneticist after the genetic counseling session. High-risk individuals should be followed oncology clinics or by other specialists.

Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case-control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI. Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls. Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m 2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04-1.14; P = 0.007]. We observed significant heterogeneity by study design ( P = 0.04), noting the BMI-multiple myeloma association only for population-based studies ( P trend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m 2 ; OR, 1.2; 95% CI, 1.1-1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI ( P interaction <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25-<30 kg/m 2 ) or obese (30+ kg/m 2 ) in both younger and usual adulthood (vs. individuals consistently <25 kg/m 2 ), but not for those overweight or obese at only one time period. Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood. Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objectives: We aimed to evaluate the relation between menstrual and reproductive factors, exogenous hormones, and risk of pancreatic cancer (PC)., Methods: Eleven case-control studies within the International Pancreatic Cancer Case-control Consortium took part in the present study, including in total 2838 case and 4748 control women. Pooled estimates of odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using a 2-step logistic regression model and adjusting for relevant covariates., Results: An inverse OR was observed in women who reported having had hysterectomy (ORyesvs.no, 0.78; 95% CI, 0.67-0.91), remaining significant in postmenopausal women and never-smoking women, adjusted for potential PC confounders. A mutually adjusted model with the joint effect for hormone replacement therapy (HRT) and hysterectomy showed significant inverse associations with PC in women who reported having had hysterectomy with HRT use (OR, 0.64; 95% CI, 0.48-0.84)., Conclusions: Our large pooled analysis suggests that women who have had a hysterectomy may have reduced risk of PC. However, we cannot rule out that the reduced risk could be due to factors or indications for having had a hysterectomy. Further investigation of risk according to HRT use and reason for hysterectomy may be necessary., Competing Interests: The authors have no conflicts of interest to report

The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of "bonafide" breast cancer susceptibility genes.

Background: Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and ultraviolet (UV) light exposure, and they cluster mutually in families (though not in individuals). We speculated if in addition to sharing environmental risk factors, MS and HL were also genetically related. Using data from genome-wide association studies (GWAS) of 1816 HL patients, 9772 MS patients and 25 255 controls, we therefore investigated the genetic overlap between the two diseases., Methods: From among a common denominator of 404 K single nucleotide polymorphisms (SNPs) studied, we identified SNPs and human leukocyte antigen (HLA) alleles independently associated with both diseases. Next, we assessed the cumulative genome-wide effect of MS-associated SNPs on HL and of HL-associated SNPs on MS. To provide an interpretational frame of reference, we used data from published GWAS to create a genetic network of diseases within which we analysed proximity of HL and MS to autoimmune diseases and haematological and non-haematological malignancies., Results: SNP analyses revealed genome-wide overlap between HL and MS, most prominently in the HLA region. Polygenic HL risk scores explained 4.44% of HL risk (Nagelkerke R(2)), but also 2.36% of MS risk. Conversely, polygenic MS risk scores explained 8.08% of MS risk and 1.94% of HL risk. In the genetic disease network, HL was closer to autoimmune diseases than to solid cancers., Conclusions: HL displays considerable genetic overlap with MS and other autoimmune diseases., (© The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations., Methods: We conducted a pooled analysis of seven case-control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses., Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68-1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80-1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37-1.15, I(2) = 76.0%, Pheterogeneity = 0.01)., Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis., Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology., (©2015 American Association for Cancer Research.)

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.

Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates., Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center., Results: Neither ever smokers (OR, 0.95; 95% CI, 0.87-1.05), current smokers (OR, 0.82; 95% CI, 0.73-0.93), nor former smokers (OR, 1.03; 95% CI, 0.92-1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups., Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma., Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631-4. ©2014 AACR., (©2014 American Association for Cancer Research.)

Background: Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma., Methods: To better understand this relationship, we conducted an analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls). Summary ORs and 95% confidence intervals (CI) relating different measures of alcohol consumption and multiple myeloma risk were computed by unconditional logistic regression with adjustment for age, race, and study center., Results: Cases were significantly less likely than controls to report ever drinking alcohol (men: OR = 0.72; 95% CI, 0.59-0.89; women: OR = 0.81; 95% CI, 0.68-0.95). The inverse association with multiple myeloma was stronger when comparing current to never drinkers (men: OR = 0.57; 95% CI, 0.45-0.72; women: OR = 0.55; 95% CI, 0.45-0.68), but null among former drinkers. We did not observe an exposure-response relationship with increasing alcohol frequency, duration, or cumulative lifetime consumption. Additional adjustment for body mass index, education, or smoking did not affect our results; and the patterns of association were similar for each type of alcohol beverage examined., Conclusions: Our study is, to our knowledge, the largest of its kind to date, and our findings suggest that alcohol consumption may be associated with reduced risk of multiple myeloma., Impact: Prospective studies, especially those conducted as pooled analyses with large sample sizes, are needed to confirm our findings and further explore whether alcohol consumption provides true biologic protection against this rare, highly fatal malignancy., (©2013 AACR.)

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.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the occurrence of juvenile polyps and predisposition to cancer of the gastrointestinal tract (GIT). Characteristic feature of juvenile polyps are irregular cystic glands filled with mucus not observed in other colorectal cancer syndromes. Germline mutations in the SMAD4 and BMPR1A genes are found in 40% of the JP individuals. Hereditary hemorrhagic telangiectasia (HHT) and higher frequency of gastric polyposis are associated mostly with SMAD4 mutations.

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.

Backgrounds: Cowden syndrome (CS) is a rare autosomal dominant disorder with an increased risk of breast, thyroid and uterine cancer development. The International Cowden Consortium has defined strict diagnostic criteria for individuals and families suspected of having CS., Patients and Methods: We analyzed the genomic DNA of 16 patients by sequencing analysis and MLPA (multiplex ligation-dependent probe amplification) method., Results: We found germline mutations, c.825&#95;840del, resp. c.438delT, in 2 patients. Both patients fulfilled strict diagnostic criteria. The other patients, except one, who did not fulfil the criteria, did not harbour any pathogenic mutation. Patients not fulfilling strict diagnostic criteria were included in the study according to major CS criteria but not pathogenic., Conclusion: Our results and information from relevant articles show that strict international criteria are well established and analysis of "CS-like" patients has no significant prognostic meaning.

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.