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1.
Klin Onkol ; 37(6): 431-439, 2023.
Article in English | MEDLINE | ID: mdl-38158231

ABSTRACT

BACKGROUND: Hereditary cancer syndromes are an important subset of malignant cancers caused by pathogenic variants in one of many known cancer predisposition genes. Diagnosis of cancer predisposition is based on genetic testing using next-generation sequencing. This allows many genes to be analysed at once, increasing the number of variants identified. The correct classification of the variants found is essential for the clinical interpretation of genetic test results. PURPOSE: The aim of this study is to summarise the rules for classifying identified variants within individual laboratories and to present the process for creating a common classification. In the Czech Republic, the sharing of identified genetic variants and the development of their consensus classification among national laboratory diagnostic communities is carried out within the Czech Cancer Panel for Clinical Application (CZECANCA) consortium of scientific and diagnostic oncogenetic laboratories. Consensus for variant classification follows a defined protocol. Sharing the results and consensus classification accelerates and refines the release of genetic test results, harmonises results between laboratories and thus contributes to improving the care of individuals at high risk of cancer and their relatives.


Subject(s)
Genetic Predisposition to Disease , Neoplastic Syndromes, Hereditary , Humans , Consensus , Genetic Testing/methods , Germ-Line Mutation , Neoplastic Syndromes, Hereditary/genetics , Germ Cells
2.
Klin Onkol ; 36(3): 198-205, 2023.
Article in English | MEDLINE | ID: mdl-37353348

ABSTRACT

BACKGROUND: Breast cancer is a complex, multifactorial disease influenced by many genetic factors. Besides the relatively rare pathogenic variants in high or moderate penetrant cancer predisposition genes, breast cancer risk is modified by numerous low risk alleles considered to be polygenic genetic factors. While the risks associated with individual polygenic loci are negligible, its cumulative effect can reach clinically significant values and it can be expressed as a polygenic risk score (PRS). PRS is recently considered to be a possible tool improving assessment of absolute and cumulative risks at the individual level. PURPOSE: Several single nucleotide polymorphism sets for PRS assessment have recently been developed and prepared for their implementation into clinical practice. The following text aims to explain the fundamental principles of the PRS assessment and its interpretation as a candidate prediction tool. The use of the PRS should always depend on genetic analysis of pathogenic variants in cancer predisposition genes including its current limitations.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Genetic Predisposition to Disease , Risk Factors , Risk Assessment , Multifactorial Inheritance
3.
Physiol Res ; 71(2): 305-315, 2022 04 30.
Article in English | MEDLINE | ID: mdl-35275695

ABSTRACT

Balance control is a critical task of daily life, the ability to maintain upright posture becomes of particular concern during aging when the sensory and motor system becomes deteriorated. Falls contribute to the most deaths caused by injury within the aged population, and the mortality rate following a fall is drastically elevated. Longitudinal and reliable assessment of balance control abilities is a critical point in the prediction of increased risk of falling in an elderly population. The primary aim of the study was to evaluate the efficiency of the Homebalance test in the identification of persons being at higher risk of falling. 135 subjects (82 women and 53 men) with geriatric syndrome have been recruited and the Homebalance and the Tinetti Balance test were performed. Results of both tests strongly correlated proving the good performance of the Homebalance test. Standing balance declines with increasing body mass index in both genders. Analysis of fluctuations of the center of pressure (COP) revealed higher frequency and magnitude in mediolateral direction COP movements when compared women to men. A strong negative correlation has been found between Tinetti static balance score and the total length of the COP trajectory during the examination on Homebalance (r = -0.6, p<0.001). Although both methods revealed good performance in detecting balance impairment, Homebalance test possesses higher precision due to the continuous nature of COP-derived parameters. In conclusion, our data proved that the Homebalance test is capable to identify persons with impaired balance control and thus are at higher risk of falling.


Subject(s)
Accidental Falls , Postural Balance , Accidental Falls/prevention & control , Adult , Aged , Aging , Body Mass Index , Female , Humans , Male
5.
Cancer Genet ; 209(5): 199-204, 2016 May.
Article in English | MEDLINE | ID: mdl-27106063

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common solid cancer diagnoses. It has been shown that up to 10% of PDAC cases have a familial component. Characterization of PDAC-susceptibility genes could reveal high-risk individuals and patients that may benefit from tailored therapy. Hereditary mutations in PALB2 (Partner and Localizer of BRCA2) gene has been shown to predispose, namely to PDAC and breast cancers; however, frequencies of mutations vary among distinct geographical populations. Using the combination of sequencing, high-resolution melting and multiplex ligation-dependent probe amplification analyses, we screened the entire PALB2 gene in 152 unselected Czech PDAC patients. Truncating mutations were identified in three (2.0%) patients. Genotyping of found PALB2 variants in 1226 control samples revealed one carrier of PALB2 truncating variant (0.08%; P = 0.005). The mean age at PDAC diagnosis was significantly lower among PALB2 mutation carriers (51 years) than in non-carriers (63 years; P = 0.016). Only one patient carrying germline PALB2 mutation had a positive family breast cancer history. Our results indicate that hereditary PALB2 mutation represents clinically considerable genetic factor increasing PDAC susceptibility in our population and that analysis of PALB2 should be considered not only in PDAC patients with familial history of breast or pancreatic cancers but also in younger PDAC patients without family cancer history.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Mutation , Nuclear Proteins/genetics , Pancreatic Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Czech Republic/epidemiology , DNA Mutational Analysis , Fanconi Anemia Complementation Group N Protein , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Pancreatic Neoplasms/epidemiology
6.
Clin Genet ; 90(4): 324-33, 2016 10.
Article in English | MEDLINE | ID: mdl-26822949

ABSTRACT

Hereditary breast cancer comprises a minor but clinically meaningful breast cancer (BC) subgroup. Mutations in the major BC-susceptibility genes are important prognostic and predictive markers; however, their carriers represent only 25% of high-risk BC patients. To further characterize variants influencing BC risk, we performed SOLiD sequencing of 581 genes in 325 BC patients (negatively tested in previous BRCA1/BRCA2/PALB2 analyses). In 105 (32%) patients, we identified and confirmed 127 truncating variants (89 unique; nonsense, frameshift indels, and splice site), 19 patients harbored more than one truncation. Forty-six (36 unique) truncating variants in 25 DNA repair genes were found in 41 (12%) patients, including 16 variants in the Fanconi anemia (FA) genes. The most frequent variant in FA genes was c.1096_1099dupATTA in FANCL that also show a borderline association with increased BC risk in subsequent analysis of enlarged groups of BC patients and controls. Another 81 (53 unique) truncating variants were identified in 48 non-DNA repair genes in 74 patients (23%) including 16 patients carrying variants in genes coding proteins of estrogen metabolism/signaling. Our results highlight the importance of mutations in the FA genes' family, and indicate that estrogen metabolism genes may reveal a novel candidate genetic component for BC susceptibility.


Subject(s)
Breast Neoplasms/genetics , DNA Repair/genetics , Mutation , Aged , Aged, 80 and over , BRCA1 Protein/genetics , BRCA2 Protein/genetics , DNA Mutational Analysis , Fanconi Anemia Complementation Group L Protein/genetics , Fanconi Anemia Complementation Group N Protein , Female , Humans , Middle Aged , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics
7.
Klin Onkol ; 29 Suppl 1: S31-4, 2016.
Article in Czech | MEDLINE | ID: mdl-26691940

ABSTRACT

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.


Subject(s)
Genetic Testing , Mutation , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics , Breast Neoplasms/genetics , Fanconi Anemia Complementation Group N Protein , Female , Humans
8.
Klin Onkol ; 29 Suppl 1: S46-54, 2016.
Article in Czech | MEDLINE | ID: mdl-26691942

ABSTRACT

Individuals with hereditary cancer syndromes form a minor but clinically important subgroup of oncology patients, comprising several thousand cases in the Czech Republic annually. In these patients, the identification of pathogenic mutations in cancer susceptibility genes has an important predictive and, in some cases, prognostic value. It also enables rational preventive strategies in asymptomatic carriers from affected families. More than 150 cancer susceptibility genes have been described so far; however, mutations in most of them are very rare, occurring with substantial population variability, and hence their clinical interpretation is very complicated. Diagnostics of mutations in cancer susceptibility genes have benefited from the broad availability of next-generation sequencing analyses using targeted gene panels. In order to rationalize the diagnostics of hereditary cancer syndromes in the Czech Republic, we have prepared the sequence capture panel "CZECANCA", targeting 219 cancer susceptibility genes. Besides more than 50 clinically important high- and moderate-penetrance susceptibility genes, the panel also targets less common candidate genes with uncertain clinical relevance. Alongside the panel design, we have optimized the analytical and bioinformatics pipeline, which will facilitate establishing a collective nationwide database of genotypes and clinical data from the analyzed individuals. The key objective of this project is to provide diagnostic laboratories in the Czech Republic with a reliable procedure and collective database improving the clinical utility of next-generation sequencing analyses in high-risk patients, which would help improve the interpretation of rare or population-specific variants in cancer susceptibility genes.


Subject(s)
Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Neoplasms/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Humans , Neoplasms/etiology
9.
Klin Onkol ; 25 Suppl: S59-66, 2012.
Article in Czech | MEDLINE | ID: mdl-22920209

ABSTRACT

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.


Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease , Genetic Testing , Ataxia Telangiectasia Mutated Proteins , Breast Neoplasms/diagnosis , Cell Cycle Proteins/genetics , Checkpoint Kinase 2 , DNA-Binding Proteins/genetics , Fanconi Anemia Complementation Group N Protein , Female , Genes, BRCA1 , Genes, BRCA2 , Genes, Tumor Suppressor , Humans , Mutation , Nuclear Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics
10.
Neoplasma ; 57(3): 280-5, 2010.
Article in English | MEDLINE | ID: mdl-20353281

ABSTRACT

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.


Subject(s)
Breast Neoplasms/genetics , Genes, BRCA1 , Genes, BRCA2 , Genetic Carrier Screening , Mutation , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Humans , Middle Aged
11.
Prague Med Rep ; 105(2): 111-8, 2004.
Article in English | MEDLINE | ID: mdl-15782560

ABSTRACT

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.


Subject(s)
Breast Neoplasms/genetics , Microsatellite Repeats , Breast Neoplasms/diagnosis , Female , Genetic Markers , Humans , Loss of Heterozygosity
12.
Neoplasma ; 50(4): 246-50, 2003.
Article in English | MEDLINE | ID: mdl-12937835

ABSTRACT

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.


Subject(s)
Acrylic Resins , Carrier Proteins/genetics , DNA Mutational Analysis/methods , Genes, BRCA1 , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Carrier Proteins/metabolism , DNA Primers/chemistry , DNA, Neoplasm/analysis , Female , Humans , Mass Screening/methods , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/genetics , Polymerase Chain Reaction , Ubiquitin-Protein Ligases
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