The current study assessed the performance of the fully automated RT-PCR-based IdyllaTM GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers. The IdyllaTM GeneFusion Assay detects fusions using fusion-specific as well as expression imbalance detection, the latter enabling detection of uncommon fusions not covered by fusion-specific assays. In total, 326 archival aNSCLC formalin-fixed paraffin-embedded (FFPE) samples were included of which 44% were resected specimen, 46% tissue biopsies, and 9% cytological specimen. With a total of 179 biomarker-positive cases (i.e., 85 ALK, 33 ROS1, 20 RET fusions and 41 MET exon 14 skipping), this is one of the largest fusion-positive datasets ever tested. The results of the IdyllaTM GeneFusion Assay were compared with earlier results of routine reference technologies including fluorescence in situ hybridization, immunohistochemistry, reverse-transcription polymerase chain reaction, and next-generation sequencing, establishing a high sensitivity/specificity of 96.1%/99.6% for ALK, 96.7%/99.0% for ROS1, 100%/99.3% for RET fusion, and 92.5%/99.6% for MET exon 14 skipping, and a low failure rate (0.9%). The IdyllaTM GeneFusion Assay was found to be a reliable, sensitive, and specific tool for routine detection of ALK, ROS1, RET fusions and MET exon 14 skipping. Given its short turnaround time of about 3 h, it is a time-efficient upfront screening tool in FFPE samples, supporting rapid clinical decision making. Moreover, expression-imbalance-based detection of potentially novel fusions may be easily verified with other routine technologies without delaying treatment initiation.

• MeSH
• anaplastická lymfomová kináza * genetika   MeSH
• exony * genetika   MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• genová přestavba MeSH
• hybridizace in situ fluorescenční metody   MeSH
• lidé MeSH
• multiplexová polymerázová řetězová reakce MeSH
• nádorové biomarkery genetika   analýza   MeSH
• nádory plic * genetika   patologie   MeSH
• nemalobuněčný karcinom plic * genetika   patologie   MeSH
• protoonkogenní proteiny c-met * genetika   MeSH
• protoonkogenní proteiny c-ret * genetika   MeSH
• protoonkogenní proteiny * genetika   MeSH
• tyrosinkinasy * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• multicentrická studie MeSH

Východiska: Skipping mutace exonu 14 faktoru mezenchymálně-epiteliální tranzice (MET) byla v klinické praxi nedávno označena jako stěžejní gen u nemalobuněčného karcinomu plic (non-small cell lung cancer – NSCLC). V klinických studiích několika inhibitorů MET byla prokázána jejich účinnost u pacientů s NSCLC se skipping mutací MET exonu 14. Pokud je nám ale známo, v těchto studiích nebyl žádný pacient s jedinou skipping mutací MET exonu 14, který by rychle progredoval a měl špatnou prognózu. Případ: Muž ve věku 61 let si stěžoval na bolesti v dorsu levé nohy a v levém lokti. CT hrudníku odhalila masu v pravém dolním laloku plic a FDG-PET prokázala metastázy v žebrech, hrudní páteři, levém lokti a levé metakarpální kosti. Korigovaná hladina vápníku byla zvýšena až na 14,1 mg/dl. Histopatologie vzorků transbronchiální biopsie morfologicky odpovídala spinoceulárnímu karcinomu. Skipping mutace MET exonu 14 byla v systému Oncomine Dx Target Test Multi-CDx pozitivní. Během několika málo týdnů po přijetí pacientův stav dýchacího traktu rapidně zhoršil karcinomatózní lymfangiózu a za měsíc od přijetí do nemocnice pacient zemřel na akutní respirační selhání. U tohoto pacienta byly také zjištěny metastázy do netypických míst a hyperkalcemie. Závěr: Pulmologové by měli mít na paměti, že mezi pacienty se skipping mutacemi MET exonu 14 mohou být rychle progredující pacienti s fatálním vývojem onemocnění.

Background: The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation has recently emerged as a driver gene in non-small cell lung cancer (NSCLC) in clinical practice. Clinical trials of several MET inhibitors have shown the effectiveness of MET inhibitors in NSCLC patients with MET exon 14 skipping mutation. To the best of our knowledge, however, there was no patient with sole MET exon 14 skipping mutation who progressed rapidly and had a poor prognosis. Case: A 61-year-old man presented with pain in the dorsum of the left foot and in the left elbow. Chest CT revealed a mass in the right lower lobe of the lung, and FDG-PET showed metastases in the ribs, thoracic vertebra, left elbow, and left metacarpal bone. Corrected calcium level was elevated up to 14.1 mg/dL. The histopathology of the transbronchial biopsy specimen was morphologically consistent with squamous cell carcinoma. MET exon 14 skipping mutation was positive in Oncomine Dx Target Test Multi-CDx system. Within a few weeks of admission, the patient‘s respiratory condition rapidly deteriorated carcinomatous lymphangiosis and died of acute respiratory failure one month after admission. In this patient, bone metastases to atypical sites and hypercalcemia were also observed. Conclusion: Chest physicians should be noted that there might be rapidly progressive fatal patients among those with MET exon 14 skipping mutations.

• MeSH
• epitelové buňky patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mutace MeSH
• nádory kostí sekundární   MeSH
• nemalobuněčný karcinom plic * genetika   patologie   MeSH
• progrese nemoci MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• smrt MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Background: Pediatric papillary thyroid carcinoma (PTC) is a rare malignancy, but with increasing incidence. Pediatric PTCs have distinct clinical and pathological features and even the molecular profile differs from adult PTCs. Somatic point mutations in pediatric PTCs have been previously described and studied, but complex information about fusion genes is lacking. The aim of this study was to identify different fusion genes in a large cohort of pediatric PTCs and to correlate them with clinical and pathological data of patients. Methods: The cohort consisted of 93 pediatric PTC patients (6-20 years old). DNA and RNA were extracted from fresh frozen tissue samples, followed by DNA and RNA-targeted next-generation sequencing analyses. Fusion gene-positive samples were verified by real-time polymerase chain reaction. Results: A genetic alteration was found in 72/93 (77.4%) pediatric PTC cases. In 52/93 (55.9%) pediatric PTC patients, a fusion gene was detected. Twenty different types of RET, NTRK3, ALK, NTRK1, BRAF, and MET fusions were found, of which five novel, TPR/RET, IKBKG/RET, BBIP1/RET, OPTN/BRAF, and EML4/MET, rearrangements were identified and a CUL1/BRAF rearrangement that has not been previously described in thyroid cancer. Fusion gene-positive PTCs were significantly associated with the mixture of classical and follicular variants of PTC, extrathyroidal extension, higher T classification, lymph node and distant metastases, chronic lymphocytic thyroiditis, and frequent occurrence of psammoma bodies compared with fusion gene-negative PTCs. Fusion-positive patients also received more doses of radioiodine therapy. The most common fusion genes were the RET fusions, followed by NTRK3 fusions. RET fusions were associated with more frequent lymph node and distant metastases and psammoma bodies, and NTRK3 fusions were associated with the follicular variant of PTC. Conclusions: Fusion genes were the most common genetic alterations in pediatric PTCs. Fusion gene-positive PTCs were associated with more aggressive disease than fusion gene-negative PTCs.

• MeSH
• bodová mutace MeSH
• dítě MeSH
• fenotyp MeSH
• fúze genů * MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory štítné žlázy genetika   patologie   terapie   MeSH
• papilární karcinom štítné žlázy genetika   patologie   terapie   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• receptor trkA genetika   MeSH
• receptor trkC genetika   MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related deaths worldwide. Various molecular markers in NSCLC patients have been developed, including gene rearrangements, currently used in therapeutic strategies. With increasing number of these molecular biomarkers of NSCLC, there is a demand for highly efficient methods for detecting mutations and translocations in treatable targets. Those currently available U.S. Food and Drug Administration (FDA) approved approaches, for example imunohistochemisty (IHC) and fluorescence in situ hybridization (FISH), are inadequate, due to sufficient quantity of material and long time duration. Next-generation massive parallel sequencing (NGS), with the ability to perform and capture data from millions of sequencing reactions simultaneously could resolve the problem. Thanks to gradual NGS introduction into clinical laboratories, screening time should be considerably shorter, which is very important for patients with advanced NSCLC. Moreover, only a minimum sample input is needed for achieving adequate results. NGS was compared to the current detection methods of ALK, ROS1, c-RET and c-MET rearrangements in NSCLC and a significant match, between IHC, FISH and NGS results, was found. Recent available researches have been carried out on a small numbers of patients. Verifying these results on larger patients cohort is important. This review sumarizes the literature on this subject and compares current possibilities of predictive gene rearrangements detection in patients with NSCLC.

• MeSH
• anaplastická lymfomová kináza genetika   MeSH
• cílená molekulární terapie MeSH
• genová přestavba genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádory plic diagnóza   genetika   MeSH
• nemalobuněčný karcinom plic diagnóza   genetika   MeSH
• onkogenní fúze genetika   MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• sekvenční analýza DNA MeSH
• sekvenční analýza RNA MeSH
• translokace genetická genetika   MeSH
• tyrosinkinasy genetika   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

• MeSH
• analýza přežití MeSH
• anaplastická lymfomová kináza genetika   metabolismus   MeSH
• epigenomika metody   MeSH
• gliom klasifikace   genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA * MeSH
• nádory mozku klasifikace   genetika   metabolismus   MeSH
• novorozenec MeSH
• protoonkogenní proteiny c-met genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• receptor trkA genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• sekvenování exomu metody   MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• tyrosinkinasy genetika   metabolismus   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) ligand/receptor axis has been implicated in pathogenesis of malignant diseases including squamous cell carcinoma of the head and neck (SCCHN). Overexpression of c-MET has been reported as a common molecular abnormality in SCCHN, although its prognostic and predictive value remains to be validated. METHODS: We systematically searched literature for studies evaluating c-MET expression on immunohistochemistry in newly diagnosed, non-metastatic SCCHN. The c-MET expressing cases were classified into three categories according to predefined cut-off values for positivity. Our aim was to assess the prevalence of c-MET expression and its relationship with selected clinicopathological variables. RESULTS: Twenty-eight studies with 2019 cases were included. Relative frequencies of c-MET expression above cut-off levels I, II, and III were 81.8%, 63.8%, and 46.2%, respectively. Differences between these three values were statistically significant (p<1.0×10-6). Above cut-off level II, c-MET positivity was associated with worse overall survival (p=4.0×10-6), positive nodal status (p=1.0×10-4), higher disease stage (p=7.0×10-4), older age (p=2.1×10-3), disease recurrence (p=2.0×10-2), and primary tumour localization in the oral cavity (p=2.3×10-2). Above cut-off level III, c-MET positivity was associated with worse disease-free or progression-free survival (p=9.0×10-6), p16 negativity (p=2.4×10-4), worse overall survival (p=4.0×10-4), positive epidermal growth factor receptor (EGFR) status (p=7.2×10-4), and larger primary tumours (p=4.6×10-3). CONCLUSION: In SCCHN, immunohistochemical overexpression of c-MET above cut-off levels III and particularly II was associated with inferior survival outcomes and advanced disease. Moreover, it represents a promising predictive biomarker for c-MET targeting, yet the optimal scoring method remains to be defined.

• MeSH
• analýza přežití MeSH
• epitelo-mezenchymální tranzice MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory hlavy a krku genetika   patologie   patofyziologie   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-met genetika   fyziologie   MeSH
• spinocelulární karcinom genetika   patologie   patofyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

• MeSH
• cholangiokarcinom genetika   virologie   MeSH
• geny erbB-1 * MeSH
• hemangiosarkom genetika   virologie   MeSH
• hepatocelulární karcinom genetika   virologie   MeSH
• integrace viru MeSH
• inzerční mutageneze * MeSH
• karcinogeneze * MeSH
• kur domácí genetika   MeSH
• lidé MeSH
• nádory jater genetika   virologie   MeSH
• onkogeny MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• proviry genetika   fyziologie   MeSH
• ptačí proteiny genetika   MeSH
• tyrosinkinasové receptory genetika   MeSH
• virus ptačí myeloblastózy genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Even after successful radical treatment of lung cancer, patients in stages I and II of the TNM system very frequently suffer recurrence, which end lethally. Detection of subclinical residual disease after surgery is thus one of the most important emerging diagnostic methods. Minimal residual disease (MRD) is defined as the presence of isolated tumor cells or circulating cells in a patient after curative primary tumor removal and at the same time, no clinical signs of cancer. Conventional methods cannot detect minimal residual disease and hence there is a need for detection using new molecular biological methods. METHODS: We searched the PubMed database for original and review articles on minimal residual disease in lung cancer. Search words were "lung cancer", "minimal residual disease" and "detection of minimal residual disease". The publications we found were compared with the results of our own studies on the detection of minimal residual disease in lung cancer and the personal experiences are described. Examination of blood samples from 98 healthy volunteers and bone marrow from 12 patients with non inflammatory and non tumour illness, were used to determine cut-off values for specific markers in the compartments. Subsequently, expression of selected markers in tumor tissue was analysed in a pilot sample of 50 patients with lung cancer and the presence of MRD was measured as expression of values of the tested markers correlated with clinico-pathological characteristics. CONCLUSIONS: Recent studies on other malignancies apart from lung cancer have shown the importance of MRD detection in the determination of disease progression and prognosis. The methods of MRD diagnostics are based on detection of specific tumor markers. Of these, the most specific for lung cancer, appears to be the LunX protein. The best method for determining MRD is probably RT-PCR. Further studies should expand knowledge in this area: to refine understanding of the importance of tumor markers for prognosis, as well as to confirm the significance of these findings in clinical practice.

• MeSH
• erbB receptory genetika   MeSH
• fosfoproteiny genetika   MeSH
• glykoproteiny genetika   MeSH
• keratin-19 genetika   MeSH
• lidé MeSH
• messenger RNA krev   MeSH
• nádorové biomarkery krev   MeSH
• nádorové cirkulující buňky * MeSH
• nádory plic krev   diagnóza   chirurgie   MeSH
• nemalobuněčný karcinom plic krev   diagnóza   chirurgie   MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• reziduální nádor MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer that is the leading cause of cancer-related mortality worldwide. Several predictive markers have Been found in NSCLC patients to date But only a few are currently used for tailored therapy. METHODS AND RESULTS: Pu BMed and We B of Science online data Bases were used to search review and original articles on the most important predictive markers in NSCLC. CONCLUSION: EGFR activating mutations (exons 18 to 21) and EML4-ALK rearrangement are clinically important markers a Ble to select NSCLC patients which Benefit from EGFR or ALK tyrosine kinase inhi Bitors (gefitini B, erlotini B, crizotini B). Other markers, such as KRAS mutation, EGFR T790M mutation and C-MET amplification, are responsi Ble for resistance to these inhi Bitors. Overcoming of this resistance as well as discovery of new potential markers and inhi Bitors is the main goal of ongoing research and clinical trials in NSCLC.

• MeSH
• chemorezistence MeSH
• erbB receptory účinky léků   genetika   MeSH
• fúzní onkogenní proteiny účinky léků   genetika   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• protoonkogenní proteiny c-met účinky léků   genetika   MeSH
• protoonkogenní proteiny účinky léků   genetika   MeSH
• ras proteiny účinky léků   genetika   MeSH
• tyrosinkinasy účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• DNA-helikasy analýza   diagnostické užití   genetika   MeSH
• exprese genu genetika   MeSH
• geny BRCA1 MeSH
• geny erbB-1 genetika   MeSH
• geny erbB-2 genetika   MeSH
• geny p53 genetika   MeSH
• geny pX genetika   MeSH
• inhibitor p16 cyklin-dependentní kinasy analýza   diagnostické užití   genetika   MeSH
• lidé MeSH
• mikrotubulární proteiny analýza   diagnostické užití   genetika   MeSH
• mutace genetika   MeSH
• nádorové biomarkery analýza   genetika   MeSH
• nádory dýchací soustavy diagnóza   farmakoterapie   genetika   MeSH
• nádory plic diagnóza   farmakoterapie   genetika   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-met analýza   diagnostické užití   genetika   MeSH
• ribonukleasy analýza   diagnostické užití   genetika   MeSH
• thymidylátsynthasa analýza   diagnostické užití   genetika   MeSH
• tubulin analýza   diagnostické užití   genetika   MeSH
• Check Tag
• lidé MeSH