Predisposition
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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.
- MeSH
- checkpoint kinasa 2 genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genetické testování MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu u mužů * genetika MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- senioři MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- poruchy příjmu potravy etiologie MeSH
- rizikové faktory MeSH
- stravovací zvyklosti psychologie MeSH
- Publikační typ
- kongresy MeSH
2nd ed. xxii, 441 s. : il. ; 28 cm
Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.
- MeSH
- checkpoint kinasa 2 chemie genetika metabolismus MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- mutační rychlost MeSH
- nádory enzymologie genetika MeSH
- substrátová specifita MeSH
- zárodečné mutace genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Inborn errors of immunity (IEI) are genetically and clinically heterogeneous disorders that, in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next-generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with Epstein-Barr virus susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that, when present in the germline, cause IEI with cancer predisposition but, when arising as somatic variants, behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat IEI.
- MeSH
- genetická predispozice k nemoci MeSH
- genomika MeSH
- infekce virem Epsteina-Barrové * MeSH
- lidé MeSH
- nádory * diagnóza genetika terapie MeSH
- virus Epsteinův-Barrové MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
Již více než 10 let se řadí diabetes mellitus a diabetická nefropatie (DN) mezi komplexní onemocnění, u kterých není možné vytvořit jednoduchý mendelovský model. Etiopatogeneze těchto chorob je multifaktoriální: individuální genetická predispozice, daná monogenními i polygenními faktory, je po ovlivnění vnějším prostředím (fyzická aktivita, dieta, nadváha, klima, metabolická kontrola) předpokladem k určité fenotypické expresi. Uvažovanou možností je také varianta, že je dána genetická predispozice k rozvoji chronické renální insuficience (CHRI) jako takové bez ohledu na základní onemocnění. V genetickém výzkumu genů zodpovědných za vznik DN se v současné době používají zejména asociační studie a vazebné studie. Asociační studie srovnávají výskyt polymorfismů kandidátních genů mezi skupinou nepříbuzných postižených jedinců a skupinou zdravých kontrol. V principu sledují, jestli jsou zjištěné rozdíly statisticky významné. Asociačními studiemi byly dosud zkoumány geny zapojené do mechanismů, které se mohou podílet na patogenezi DN a souvisí zejména s familiární hypertenzí a regulací krevního tlaku, transportem natria a lithia, familiární hyperlipidemií a metabolismem glukózy. Vazebné studie jsou prováděny ve dvou variantách: 1) rozsáhlé testování celého genomu pomocí kompletní sady markerů bez hypotézy kandidátního genu (poziční klonování) a 2) úzké testování daných oblastí DNA obsahujících možné kandidátní geny pomocí specifických markerů. Pro ideální vazebnou studii je nutné získat rozsáhlé rodokmeny anebo postižené sourozenecké páry.
For over a decade, diabetes mellitus and diabetic nephropathy (DN), has been perceived as complex disease for which a simple Mendelian model could not be developed. The etiopathogenesis is these diseases is multifactorial: individual genetic predisposition due to monogenic and polygenic factors becomes, after modulation by external factors (physical activity, diet, overweight, climate, metabolic control), a prerequisite for a phenotypic expression. Another plausible alternative is that genetic predisposition to the development of chronic renal insufficiency (CRI) as such is predetermined regardless of the underlying disease. Genetic research into the genes responsible for the development of DN currently uses mainly association studies and linkage studies. Association studies compare the incidence of candidate gene polymorphisms between a group of unrelated affected individuals and that of health controls. In principle, the studies are designed to determine whether or not the differences are significant. To date, association studies have been used to investigate genes involved in mechanisms which could possibly play a role in the pathogenesis of DN and are primarily related to familiar hypertension and blood pressure control, sodium and lithium transport, and glucose metabolism. There are two types of linkage studies: 1) extensive testing of the entire genome using a complete set of markers without a candidate gene hypothesis (positional cloning); and 2) narrow testing of predefined DNA regions containing potential candidate genes using specific markers. An ideal linkage study requires extensive family trees or affected sibling pairs.
- MeSH
- aldehydreduktasa fyziologie MeSH
- diabetické nefropatie etiologie genetika MeSH
- finanční podpora výzkumu jako téma MeSH
- genetická predispozice k nemoci genetika MeSH
- glukosa metabolismus MeSH
- Indiáni Severní Ameriky MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- renin-angiotensin systém fyziologie MeSH
- synthasa oxidu dusnatého fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes.
- MeSH
- dospělí MeSH
- epiteliální ovariální karcinom genetika MeSH
- genetická predispozice k nemoci * MeSH
- geny BRCA2 MeSH
- lidé MeSH
- nádory vaječníků * patologie MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- rizikové faktory MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Písmeno „P“ v klasifikačním „PIRO“ konceptu pro sepsi znamená „predispozice“. Metody molekulární biologie umožňují zjišťovat genetické predispozice u monogenních i polygenních chorob. Sepse představuje příklad polygenního onemocnění. Stanovení genetického polymorfismu u parametrů vrozené imunity, mediátorů zánětu a hemokoagulačních faktorů představuje jeden z možných přístupů. Využití metody DNA mikročipů se stanovením genové exprese tisíců genů současně je nesmírně slibnou diagnostickou možností pro budoucnost. Nutné jsou koordinované velké studie pro racionální použití těchto diagnostických metod.
The letter ”P“ means ”predisposition“ in the PIRO concept for the staging of sepsis. Different methods of molecular biology enable us to determine the genetic predisposition in both monogenic and polygenic diseases. Sepsis represents an example of a polygenic disease. The determination of genetic polymorphism of inflammatory mediators, parameters of innate immunity and haemocoagulation factors represent just one approach. The DNA microarray technology holds a promise to monitor the interaction of thousands of genes simultaneously and represents the diagnostic tool of the future. It will be necessary to coordinate clinical trials in order to make good use of these diagnostic methods.
- MeSH
- exprese genu fyziologie genetika MeSH
- genetická predispozice k nemoci genetika MeSH
- imunita získaná od matky genetika imunologie účinky léků MeSH
- interferon gama genetika MeSH
- interleukin-1 fyziologie genetika MeSH
- interleukin-6 fyziologie genetika MeSH
- polymorfismus genetický genetika imunologie MeSH
- přehledová literatura jako téma MeSH
- sepse diagnóza etiologie genetika MeSH
- tumor nekrotizující faktory fyziologie genetika MeSH
Část karcinomů prsu a vaječníků vzniká na základě zděděné genetické dispozice, mutace, v některém z predisponujících genů. Ačkoliv je tato část relativně malá, 5–10 % všech mammárních a ovariálních karcinomů, tvoří skupinu s jasně definovaným etiologickým faktorem. Prediktivní vyšetření dosud zdravých osob z rodin s genetickou dispozicí umožňuje identifikovat vysoce ohrožené jedince a zařadit je do programu primární i sekundární prevence malignit. Následující článek podává základní přehled o hereditární dispozici ke vzniku karcinomu prsu a ovaria a zaměřuje se především na geny BRCA1 a BRCA2, které jsou zodpovědné za téměř tři čtvrtiny těchto hereditárních nádorů.
Part of breast and ovarian cancer cases develops on the hereditary predisposition, i.e. mutation in one of predisposing genes. Although this proportion is relatively small, 5–10%of all breast and ovarian carcinomas, it represents a group with clearly defined etiologic factor. Predictive analysis of unaffected family members allows to identify individuals at high risk of cancer and to include them into the programme of primary and secondary cancer prevention. Following article presents basic review of the hereditary predisposition to breast and ovarian cancer focusing especially on BRCA1 and BRCA2 genes, which are responsible for almost three-quarters of those hereditary tumours.
Germline DNA testing using the next-gene-ration sequencing (NGS) technology has become the analytical standard for the diagnostics of hereditary diseases, including cancer. Its increasing use places high demands on correct sample identification, independent confirmation of prioritized variants, and their functional and clinical interpretation. To streamline these processes, we introduced parallel DNA and RNA capture-based NGS using identical capture panel CZECANCA, which is routinely used for DNA analysis of hereditary cancer predisposition. Here, we present the analytical workflow for RNA sample processing and its analytical and diagnostic performance. Parallel DNA/RNA analysis allowed credible sample identification by calculating the kinship coefficient. The RNA capture-based approach enriched transcriptional targets for the majority of clinically relevant cancer predisposition genes to a degree that allowed analysis of the effect of identified DNA variants on mRNA processing. By comparing the panel and whole-exome RNA enrichment, we demonstrated that the tissue-specific gene expression pattern is independent of the capture panel. Moreover, technical replicates confirmed high reproducibility of the tested RNA analysis. We concluded that parallel DNA/RNA NGS using the identical gene panel is a robust and cost-effective diagnostic strategy. In our setting, it allows routine analysis of 48 DNA/RNA pairs using NextSeq 500/550 Mid Output Kit v2.5 (150 cycles) in a single run with sufficient coverage to analyse 226 cancer predisposition and candidate ge-nes. This approach can replace laborious Sanger confirmatory sequencing, increase testing turnaround, reduce analysis costs, and improve interpretation of the impact of variants by analysing their effect on mRNA processing.
- MeSH
- DNA genetika MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nádory genetika diagnóza MeSH
- reprodukovatelnost výsledků MeSH
- RNA genetika MeSH
- sekvenční analýza DNA metody MeSH
- sekvenční analýza RNA metody MeSH
- vysoce účinné nukleotidové sekvenování * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
