Mucosal malignant melanoma (MMM) is a rare and aggressive tumor. Despite effective local therapies, tumor recurrence and metastasis remain frequent. The genetics of MMM remain incompletely understood. This study is aimed to identify actionable genetic alterations by next-generation sequencing. Fifteen MMM samples were analyzed by next-generation and Sanger sequencing. Gene copy number alterations were analyzed by MLPA. Mutation status was correlated with pERK, pAKT, and Ki-67 expression and follow-up data. Inactivating mutations and intragenic deletions in neurofibromatosis type-1 (NF1) were identified in 3 and 2 cases, respectively, (in total 5/15, 33%) and activating mutations in NRAS and KRAS (3/15, 20%) cases. Other mutated genes included CDKN2A, APC, ATM, MITF, FGFR1, and FGFR2. BRAF and KIT mutations were not observed. Cases with NF1 alterations tended to have worse overall survival. The mutational status was not associated with pERK, pAKT, or Ki-67 immunostaining. MMM carries frequent gene mutations activating the MAPK pathway, similar to cutaneous melanoma. In contrast, NF1 is the most frequently affected gene. Intragenic NF1 deletions have not been described before and may go undetected by sequencing studies. This finding is clinically relevant as NF1-mutated melanomas have worse survival and could benefit from therapy with immune checkpoint and MEK inhibitors.
- MeSH
- delece genu * MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- melanom genetika mortalita sekundární terapie MeSH
- mutační analýza DNA MeSH
- nádorové biomarkery genetika MeSH
- nádory vedlejších dutin nosních genetika mortalita patologie terapie MeSH
- neurofibromin 1 genetika MeSH
- nosní sliznice patologie MeSH
- prognóza MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
ABSTRACT: Primary cutaneous desmoplastic melanoma (DM) is a group of rare melanocytic tumors arising on severely sun-damaged skin, histologically characterized by the proliferation of spindled melanocytes in a prominent desmoplastic stroma, with a range of morphological presentations. In this article, we report a unique case of primary cutaneous DM composed of a nodular proliferation of highly pleomorphic spindled and epithelioid cells, pseudoglandular structures, clear cell change, and unusual collagen rosettes. Immunohistochemical analysis showed a strong and diffuse positivity for S-100 protein, SOX-10, nestin, p75 (nerve growth factor receptor), WT1, and p53. Molecular analysis detected a mutation in the NF1 gene [c.4084C > T, p.(Arg1362Ter)], 2 different pathogenic mutations in TP53 [c.742C > T, p.(Arg248Trp), AF:12%, COSM1640831 and c.528C > G, p.(Cys176Trp), AF:12%, COSM11114], and a mutation in GNAS [c.601C > T, p.(Arg201Cys), AF: 9%, COSM123397]. To the best of our knowledge, this is the first case reporting collagen rosettes and pseudoglandular features in primary cutaneous DM.
- MeSH
- chromograniny genetika MeSH
- imunohistochemie MeSH
- kolagen typu IV metabolismus MeSH
- lidé MeSH
- melanom genetika metabolismus patologie MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory kůže genetika metabolismus patologie MeSH
- neurofibromin 1 genetika MeSH
- proteiny vázající GTP - alfa-podjednotky Gs genetika MeSH
- senioři nad 80 let MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
- MeSH
- dítě MeSH
- fúzní onkogenní proteiny genetika MeSH
- genová přestavba * MeSH
- gliom klasifikace genetika patologie MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy genetika MeSH
- mladiství MeSH
- mutace * MeSH
- nádorové biomarkery genetika MeSH
- nádory mozku klasifikace genetika patologie MeSH
- neurofibromin 1 genetika MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- ras proteiny genetika MeSH
- regulace genové exprese u nádorů * MeSH
- stanovení celkové genové exprese MeSH
- variabilita počtu kopií segmentů DNA * MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later. The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors. The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render single-gene assays such as FISH impractical, and in this particular case, also insensitive.
- MeSH
- antigeny CD34 genetika metabolismus MeSH
- dospělí MeSH
- hyalin metabolismus MeSH
- koaktivátory jaderných receptorů genetika metabolismus MeSH
- lidé MeSH
- mutace MeSH
- nádory měkkých tkání genetika patologie MeSH
- neurofibromin 1 genetika MeSH
- onkogenní fúze * MeSH
- proteiny S100 genetika metabolismus MeSH
- protoonkogenní proteiny c-ret genetika metabolismus MeSH
- škára metabolismus patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Východisko. Zvýšená pravděpodobnost vzniku chromozomálních aberací u plodů matek starších 35 let je obecně známa a již 40 let je indikací k vyšetření karyotypu plodu při invazivní metodě prenatální diagnostiky, neboť genetické riziko a jeho klinický význam je podstatně vyšší než riziko spojené s nezbytnou amniocentézou. Mutagenní vliv vyššího věku otců je znám jen genetikům (1–4). Důvodem je nepochybně řádově nižší riziko vzniku čerstvých genových mutací, velké spektrum možných mutovaných genů a jen limitovaný počet autozomálně dominantně determinovaných poruch s bezprostřední manifestací po porodu. Abiotrofický charakter některých afekcí umožňuje jen omezenou nabídku jejich prevence neinvazivními metodami prenatální diagnostiky. Metody. V souboru 83 pacientů s autozomálně dominantně dědičnými syndromy spektra neurokardiofaciokutánní symptomatiky (NCFCs) jsme zhodnotili genealogická data a věk rodičů, abychom ověřili podíl tohoto mutagenního faktoru na restituci populační incidence při vysokém selekčním koeficientu (0,65). Syndrom neurokardiofaciokutánního spektra (5–7) byl zvolen po identifikaci odpovědných genů, aby mohla být na molekulární úrovni ověřena diagnóza pacientů a rozlišeny formy zděděné a mutace vzniklé de novo. Závěr. V souboru 83 pacientů s klinickou diagnózou NCFC syndromu byla u 32 detekována mutace v PTPN11 genu, u deseti mutace v SOS1 genu, u čtyř mutace v HRAS genu, u tří pacientů mutace v RAF1 genu, u dvou pacientů mutace v BRAF genu a mutace v MEK1, KRAS a NRAS genech detekována vždy u jednoho pacienta. Mutace de novo byla zjištěna u 35 pacientů a u 19 pacientů byla mutace děděna. Selekční koeficient 0,60 (29 de novo ze 48 ) byl zjištěn u pacientů s Noonanovým a LEOPARD syndromy (mutace v PTPN11, SOS1 a RAF1, KRAS a NRAS genech), syndromy Costello a kardiofaciokutánní byly ve všech šesti případech důsledkem čerstvé mutace v HRAS a BRAF genech. U 29 pacientů nemohla být diagnóza NCFC syndromu potvrzena, mutace nebyla v žádném z osmi genů detekována.
Background. Increased frequency of chromosomal aberration in children of mothers aged 35 years and older is very well known and since 1973 it is an indication to investigate the foetal karyotype in cells obtained by invasive method (amniocentesis), because the genetic risk of severe affection is higher than the risk of necessary invasive method. Mutagenic effect of advanced paternal age is known only among geneticists (1–4). The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last not least the limited spectrum of autosomal dominant disorders without abiotrofic character. Therefore the preventive methods for elimination of this risk are very limited. Only a few of them could be recognized prenatally by noninvasive methods of prenatal diagnostics. Methods. Genealogical, anamnestic and clinical data of 83 patients were studied with clinical suspection on neurocardiofaciocutaneous syndrome (NCFCs) (5–7). The diagnosis has not been confirmed in 29 patients, no mutation was detected in 8 investigated genes (PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS, NRAS). In 54 patients with autosomal dominant inherited Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome the diagnosis was confirmed on DNA level and the biological fitness was estimated for each disorder. Paternal age at conception was compared in the group of patients with familial and sporadic occurrence of Noonan and NCFC syndromes. The clinical prognosis of this disorder is represented by biological fitness of patients. Coefficient of selection is 0,6 in Noonan and LEOPARD syndromes (29 from 48). All 6 patients with Costello and cardiofaciocutaneous syndromes developed due to a new mutation. Conclusion. Paternal age at birth was studied in 83 children patients with autosomal dominant Neurocardiofaciocutaneous syndrome (Noonan, LEOPARD, Costello, CFC) with a high population incidence and decreased biological fitness. Due to severe congenital heart defects, failure to thrive in infancy, increased risk for malignancy and further health problems the clinical prognosis of patients in the past was not good. Therefore high mutation rate is expected until now. Identification of genes responsible for manifestation of this disorder, enables to confirm the diagnosis and to recognize inherited and de novo mutations. Genealogy and DNA analysis of PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS and NRAS were obtained in cohort of 54 patients with NCFC syndromes and their parents. There were 48 patients with Noonan and LEOPARD syndromes, in 29 cases due to mutation de novo, 19 patients inherited the mutation from one of parents. All 6 patients with Costello syndrome and CFC syndrome were affected due to new mutation. DNA analysis revealed 32 mutations in PTPN11 gene, mutation in SOS1 gene was found in 10 patients, RAF1 mutation was present in 3 patients; mutation in MEK1, KRAS and NRAS genes was present in one patient each. In Costello syndrome and CFC syndrome mutations in HRAS (4 patients) and BRAF (2 patients) genes were detected. Genealogic data allow analysing parental age in the group of patients with new mutation and inherited mutation. Paternal age at conception of patients with Noonan syndrome due to new mutation was significantly increased in comparison to the group of fathers of Noonan patients with inherited mutation – 38,4 years and 29,6 years, resp., range 28 to 55 years and 25 to 35 years, resp. Maternal age was slightly increased too, –30,9 and 27,7, resp. and range 24 to 42 years and 21 to 36 years, resp. but not significantly. The results support the mutagenic effect of paternal age, espec. autosomal dominant mutations.
- MeSH
- chromozomální aberace MeSH
- EDTA MeSH
- kraniofaciální abnormality * etiologie MeSH
- lidé MeSH
- mutace * genetika MeSH
- mutační analýza DNA MeSH
- mutageneze * MeSH
- neurofibromin 1 genetika MeSH
- Noonanové syndrom diagnóza genetika MeSH
- otcové MeSH
- porod MeSH
- prenatální diagnóza MeSH
- rodiče MeSH
- sekvenční analýza MeSH
- syndrom Noonanové s mnohočetnými pihami diagnóza genetika MeSH
- věk otce * MeSH
- věkové faktory * MeSH
- Check Tag
- lidé MeSH
PURPOSE OF REVIEW: To summarize the recent advances in the genetics of pheochromocytoma and paraganglioma (PHEO/PGL), focusing on the new susceptibility genes and dividing PHEOs/PGLs into two groups based on their transcription profile. RECENT FINDINGS: Recently, TMEM127, MYC-associated factor X, and hypoxia-inducible factor (HIF) 2α have been described in the pathogenesis of PHEOs/PGLs. Thus, now about 30-40% of these tumors are linked to the germline mutations, which also include mutations in the VHL, RET, NF1, SDHx, and SDHAF2 genes. Furthermore, PHEOs/PGLs have been divided into two groups, cluster 1 (SDHx/VHL) and cluster 2 (RET/NF1), based on the transcription profile revealed by genome-wide expression microarray analysis. SUMMARY: PHEOs/PGLs are the most inherited tumors among (neuro)endocrine tumors. Future approaches in genetics, including whole-genome sequencing, will allow the discovery of additional PHEO/PGL susceptibility genes. The current division of PHEOs/PGLs into cluster 1 and 2 provides us with additional knowledge related to the pathogenesis of these tumors, including the introduction of new treatment options for patients with metastatic PHEOs/PGLs. New discoveries related to the role of the HIF-1/HIF-2α genes in the pathogenesis of almost all inherited PHEOs/PGLs may call for a new regrouping of these tumors and discoveries of new treatment targets.
- MeSH
- feochromocytom genetika metabolismus terapie MeSH
- genetická predispozice k nemoci MeSH
- izoenzymy genetika metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- nádorový supresorový protein VHL genetika metabolismus MeSH
- nádory nadledvin genetika metabolismus terapie MeSH
- neurofibromin 1 genetika metabolismus MeSH
- paragangliom genetika metabolismus terapie MeSH
- protoonkogenní proteiny c-ret genetika metabolismus MeSH
- sukcinátdehydrogenasa genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
OBJECTIVES: Neurofibromatosis von Recklinghausen type 1 (NF1) is an autosomal dominant neurocutaneous disorder affecting one in 3 000-4 000 individuals. Mid-aortic syndrome (MAS) is a rare condition characterized by segmental narrowing of abdominal aorta and stenosis of its major branches - mainly renal arteries, including manifestation of renovascular hypertension. MAS can be caused by different diseases, including NF1. MAIN FINDINGS: A 9 years old girl with primary diagnosis of NF1 combined with renovascular hypertension due to MAS, suffered of bilateral optic and chiasm glioma, pubertas praecox, speech disorder, light mental retardation and scoliosis. We have found a mutation in exone 34 of the NF1 gene (17q11.2). Her father has been also diagnosed with NF1 and hypertension developed at early age. He has the same mutation in exone 34 of NF1 gene. The girl is currently treated with conservative antihypertensive medication with positive effect. Bilateral optic and chiasm glioma are asymptomatic at the time and they had been without progress over period of time. Any vascular surgery, neurosurgical and oncological therapy are not indicated at the present time. CONCLUSION: This article is a summary of clinical findings in patient with NF1 due to NF1 gene mutation in exone 34. It confirms the importance of complex multidisciplinar approach to examination and taking care of NF1 patients and their families.
- MeSH
- aorta abdominalis abnormality patologie MeSH
- arteria renalis patologie MeSH
- chiasma opticum patologie MeSH
- dítě MeSH
- financování organizované MeSH
- gliom genetika komplikace patologie MeSH
- hypertrofie levé komory srdeční genetika komplikace MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- mutace MeSH
- nádory zrakového nervu genetika komplikace patologie MeSH
- nemoci aorty genetika komplikace patologie MeSH
- neurofibromatóza 1 MeSH
- neurofibromin 1 genetika metabolismus MeSH
- předškolní dítě MeSH
- proteosyntéza MeSH
- renovaskulární hypertenze genetika komplikace patologie MeSH
- stenóza MeSH
- syndrom MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
While growth retardation and short stature are well-known features of patients with classical neurofibromatosis type 1 (NF1), we found advanced height growth and accelerated carpal bone age in patients with an NF1 microdeletion. Our analysis is based on growth data of 21 patients with common 1.4/1.2 Mb microdeletions, including three patients with a Weaver-like appearance. Overgrowth was most evident in preschool children (2-6 years, n=10, P=0.02). We conclude that childhood overgrowth is part of the phenotypic spectrum in patients with the common 1.4/1.2 Mb NF1 microdeletions and assume that the chromosomal region comprised by the microdeletions contains a gene whose haploinsufficiency causes overgrowth.
- MeSH
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- neurofibromatóza 1 etiologie genetika MeSH
- neurofibromin 1 genetika MeSH
- obličej abnormality MeSH
- předškolní dítě MeSH
- referenční hodnoty MeSH
- sekvenční delece MeSH
- tělesná výška genetika MeSH
- vývoj dítěte MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
Neurofibromatosis von Recklinghausen typ 1 (NFl) je nejčastější onemocnění ze skupiny neurokutánních syndromů, vznikajících na podkladě poruch tkáňové diferenciace (především neuroektodermu). NFl má autosomálně dominantní dědičnost, se 40-50% výskytem nových mutací a výskytem v populaci 1:3000-4000. Gen je lokalizován na 17. chromozomu (17qll.2), jeho produkt neurofíbromin redukuje buněčnou proliferaci urychlením hydrolýzy aktivního GTP-Ras na inaktivní GDP-Ras a plní tak funkci 3gativního růstového regulátoru a tumor suppressoru. Ztráta neurofibrominu ve Schwannově buňce vede k urychlení proliferace této buňky (spolu s ovlivněním proliferace fíbroblastů a mastocytů) a k tvorbě tumoru. Diagnóza NFl je určena dg. kritérii: skvrny café au lait, axilární a/nebo inguinální freckling, neurofibromy a/nebo plexiformní neurofibrom, gliom optiku, Lischovy noduly, charakteristické kostní leze (sfenoidální dysplasie, anomálie dlouhých kostí), příbuzný 1. stupně s prokázanou dg. NFl. Ke stanovení dg. NFl je třeba nalézt alespoň 2 dg. kritéria. Mezi další typické klinické nálezy u NFl patří hypersignální ložiska v T2 vážených obrazech na MRI mozku, makrocefalie, skolióza. hiálý vzrůst, specifické vývojové poruchy učení, poruchy pozornosti a chování, systémová hypertenze při fibromuskulámí dysplazii renálních arterií. Méně častejšou endokrinologické poruchy, vzácnejšou ischemické cévní mozkové příhody při postižení cév mozku. Nádorové procesy jsou převážně benigní povahy, maligní transformace je popisována ve 2-6 % případů. Terapie je především symptomatická. u progresivních lézí chirurgická, u maligních nádorů onkologická. Významná jsou režimová a výuková opatření při specifických vývojových poruchách. Prenatální diagnostika je t.č. možná s užitím nepřímé DNA analýzy u informativních rodin, přímá DNA analýza je rozvíjena.
Neurofibromatosis von Recklinghausen type 1 (NFl) is the most frequent disease from the group of neurocutaneous syndromes, resulting from disturbances of tissue differentiation (primarily neuroectoderm). NFl has autosomal dominant inheritance, with a 40-50 % incidence of new mutations and prevalence in the population 1:3000-4000. The gene is localized on chromosome 17 (17qll.2), its product neurofibromin reduces cell proliferation through acceleration of hydrolysis of the active GTP-Rás to inactive GDP-Ras and so plays a role of a negative growth regulator and tumor suppressor. Loss of neurofibromin in the Schwann cell leads to accelerated proliferation of this cell (together with influencing proliferation of fibroblasts and mastocytes) and to tumor generation. Diagnosis of NFl is determined using the following diagnostic criteria: café au lait spots, axillar and/or inguinal freckling. neurofibromas and/or plexiform neurofibroma, optic glioma, Lisch nodules, characteristic bone lesions (sphenoidal dysplasia, anomaly of long bones), first-degree relative with a confirmed diagnosis of NFl. To make diagnosis of NFl, it is necessary to fulfill at least two diagnostic criteria. Among other typical clinical findings in NFl, there are hypersignal foci in T2-weighted brain MR images, microcephaly, scoliosis, small stature, specific developmental disorders of learning, disorders of attention and behavior, systemic hypertension with fibromuscular dysplasia of renal arteries. Endocrinologic distu bances arc less frequent, rarely, ischemic strokes occur when cerebral vasculature is affected. Neoplastic processes are usually benign, malignant transformation is described in 2-6 % of cases. Therapy is primarily symptomatic, in progressive lesions also surgical, in malignant tumors oncological. Regime and education precautions are significant in specific developmental disorders. Prenatal diagnostics is currently possible using indirect DNA analysis in informative families, direct DNA analysis is being developed.
