Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.
- Publikační typ
- časopisecké články MeSH
Východiska: Hereditární nádorové syndromy tvoří významnou podskupinu zhoubných nádorových onemocnění způsobených patogenními variantami v některém z mnoha známých nádorových predispozičních genů. Diagnostika nádorové predispozice je založena na genetickém testování pomocí sekvenování nové generace. To umožňuje analýzu mnoha genů najednou, nicméně zároveň se zvyšuje počet identifikovaných variant. Správná klasifikace nalezených variant je zásadní pro klinickou interpretaci výsledků genetického testování. Cíl: Cílem práce je shrnutí pravidel pro klasifikaci identifikovaných variant v rámci jednotlivých pracovišť a představení procesu tvorby společné klasifikace. Sdílení nalezených genetických variant a tvorba jejich konsenzuální klasifikace v rámci národních laboratorně diagnostických komunit probíhá v ČR v rámci konzorcia Czech Cancer Panel for Clinical Application (CZECANCA) sdružujícího výzkumné a diagnostické onkogenetické laboratoře. Tvorba konsenzu pro klasifikaci variant probíhá podle definovaného protokolu. Sdílení výsledků a konsenzuální klasifikace zrychluje a zpřesňuje vydávání výsledků genetického testování, harmonizuje výsledky mezi laboratořemi a přispívá tak ke zkvalitnění péče o jedince ve vysokém riziku vzniku nádorových onemocnění a jejich příbuzné.
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.
- Klíčová slova
- CZECANCA,
- MeSH
- dědičné nádorové syndromy * diagnóza genetika klasifikace MeSH
- genetická predispozice k nemoci genetika prevence a kontrola MeSH
- genetické testování metody MeSH
- klasifikace MeSH
- konsensus * MeSH
- lidé MeSH
- nádory genetika klasifikace MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.
- Publikační typ
- časopisecké články MeSH
The transient receptor potential vanilloid 3 (TRPV3) channel is a Ca2+-permeable thermosensitive ion channel widely expressed in keratinocytes, where together with epidermal growth factor receptor (EGFR) forms a signaling complex regulating epidermal homeostasis. Proper signaling through this complex is achieved and maintained via several pathways in which TRPV3 activation is absolutely required. Results of recent studies have suggested that low-level constitutive activity of TRPV3 induces EGFR-dependent signaling that, in turn, amplifies TRPV3 via activation of the mitogen-activated protein kinase ERK in a positive feedback loop. Here, we explored the molecular mechanism that increases TRPV3 activity through EGFR activation. We used mutagenesis and whole-cell patch clamp experiments on TRPV3 channels endogenously expressed in an immortalized human keratinocyte cell line (HaCaT) and in transiently transfected HEK293T cells and found that the sensitizing effect of EGFR on TRPV3 is mediated by ERK. We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis.
- MeSH
- epidermální růstový faktor metabolismus MeSH
- erbB receptory agonisté metabolismus MeSH
- fosforylace účinky léků MeSH
- HEK293 buňky MeSH
- interakční proteinové domény a motivy MeSH
- kationtové kanály TRPV agonisté chemie genetika metabolismus MeSH
- keratinocyty účinky léků enzymologie metabolismus MeSH
- lidé MeSH
- MAP kinasový signální systém * účinky léků MeSH
- metoda terčíkového zámku MeSH
- mitogenem aktivovaná proteinkinasa 3 chemie genetika metabolismus MeSH
- modulátory membránového transportu farmakologie MeSH
- monoterpeny farmakologie MeSH
- mutace MeSH
- mutageneze cílená MeSH
- posttranslační úpravy proteinů účinky léků MeSH
- rekombinantní proteiny chemie metabolismus MeSH
- sloučeniny boru farmakologie MeSH
- threonin metabolismus MeSH
- transformované buněčné linie MeSH
- upregulace * účinky léků MeSH
- zelené fluorescenční proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Gain-of-function (GOF) mutations in ion channels are rare events, which lead to increased agonist sensitivity or altered gating properties, and may render the channel constitutively active. Uncovering and following characterization of such mutants contribute substantially to the understanding of the molecular basis of ion channel functioning. Here we give an overview of some GOF mutants in polymodal ion channels specifically involved in transduction of painful stimuli--TRPV1 and TRPA1, which are scrutinized by scientists due to their important role in development of some pathological pain states. Remarkably, a substitution of single amino acid in the S4-S5 region of TRPA1 (N855S) has been recently associated with familial episodic pain syndrome. This mutation increases chemical sensitivity of TRPA1, but leaves the voltage sensitivity unchanged. On the other hand, mutations in the analogous region of TRPV1 (R557K and G563S) severely affect all aspects of channel activation and lead to spontaneous activity. Comparison of the effects induced by mutations in homologous positions in different TRP receptors (or more generally in other distantly related ion channels) may elucidate the gating mechanisms conserved during evolution.
- MeSH
- bolest patofyziologie MeSH
- kationtové kanály TRP chemie genetika metabolismus MeSH
- kationtové kanály TRPV chemie genetika metabolismus MeSH
- lidé MeSH
- mícha patofyziologie MeSH
- mutace genetika MeSH
- percepce bolesti MeSH
- proteiny nervové tkáně chemie genetika metabolismus MeSH
- vápníkové kanály chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
