13 research outputs found
Új, NGS alapú módszer kidolgozása a pajzsmirigy hideg göbök malignizálódásának előrejelzésére
Targeted Mutational Profiling and a Powerful Risk Score as Additional Tools for the Diagnosis of Papillary Thyroid Cancer
Phenotypical diversity of patients with LEOPARD syndrome carrying the worldwide recurrent p.Tyr279Cys PTPN11 mutation
A pajzsmirigygöbök genetikai vizsgálata újgenerációs szekvenáláson alapuló platformon kifejlesztett génpanel segítségével = Genetic testing of thyroid nodules using a gene panel developed on a new generation sequencing platform
Absztrakt:
Bevezetés: Vékonytű-biopsziás pajzsmirigygöbminták 25%-ánál
bizonytalan citológiai eredményt kapunk. A göbök genetikai vizsgálata
hozzájárulhat a pontos diagnózishoz. Célkitűzés: Európában az
első és a legtöbb, 23 releváns pajzsmirigyonkogént (568 mutációval) tartalmazó
génpanel kialakítása. Módszer: A biopsziás mintákból izolált
DNS vizsgálata Ion Torrent újgenerációs szekvenálással történt.
Eredmények: Módszerünk validációját tumorszövetmintákon
végeztük, ennek során 127, a pajzsmirigydaganatokban eddig nem ismert
eltéréseket azonosítottunk. Az AXIN1 a legpolimorfabb génnek,
míg a BRAF c.1799T>A (V600E) a leggyakrabban azonosított
mutációnak bizonyult. A vékonytű-biopsziás mintáinkban 36-féle, klinikailag
releváns variánst detektáltunk, melyek 75%-a az irodalomban még nincs leírva. A
citológiailag malignus nyolc mintánk közül hatban, a bizonytalan citológiájú
tizennégy mintánk közül nyolcban, míg a citológiailag benignus huszonnyolc
mintánk közül húszban azonosítottunk patogén variánst valamely driver génben
(BRAF c.1799T>A, NRAS c.181C>A).
Következtetés: Olyan validált, megbízhatóan működő
újgenerációs szekvenáláson alapú módszert fejlesztettünk ki, amely nagy pozitív
prediktív értékkel (89%) és szenzitivitással (79%) képes a pajzsmirigy
rosszindulatú elváltozásainak korai felismerésére. Orv Hetil. 2019; 160(36):
1417–1425.
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Abstract:
Introduction: Twenty-five percent of fine-needle aspiration
biopsy samples of thyroid nodules produce indeterminate cytological results.
Genetic testing of nodules can contribute to accurate diagnosis.
Aim: Developing the first gene panel in Europe utilizing
the 23 most relevant thyroid oncogenes with 568 mutations.
Method: Examination of the isolated DNA from biopsy samples
by Ion Torrent new generation sequencing. Results: The
validation of our method was performed on tumor tissue samples, in which 127
genetic variations were identified, yet unknown in thyroid tumors.
AXIN1 was the most polymorphic gene, while
BRAF c.1799T>A (V600E) was the most frequently
identified mutation. We detected 36 clinically relevant variants, 75% of which
have not been described in the literature. Six of our 8 cytologically malignant
and 8 of our 14 indeterminate as well as 20 of our 28 cytologically benign
samples were identified as containing pathologic variants in a driver gene
(BRAF c.1799T>A, NRAS c.181C>A).
Conclusion: We have developed a validated, reliable new
generation sequencing-based method with high positive predictive value (89%) and
sensitivity (79%), suitable for the early detection of malignant lesions in the
thyroid. Orv Hetil. 2019; 160(36): 1417–1425
The CYLD p.R758X worldwide recurrent nonsense mutation detected in patients with multiple familial trichoepithelioma type 1, Brooke-Spiegler syndrome and familial cylindromatosis represents a mutational hotspot in the gene
Long-term selective estrogen receptor-beta agonist treatment modulates gene expression in bone and bone marrow of ovariectomized rats
Gonadal hormones including 17β-estradiol exert important protective functions in skeletal homeostasis. However, numerous details of ovarian hormone deficiency in the common bone marrow microenvironment have not yet been revealed and little information is available on the tissue-specific acts either, especially those via estrogen receptor beta (ERβ). The aim of the present study was therefore to examine the bone-related gene expression changes after ovariectomy (OVX) and long-term ERβ agonist diarylpropionitrile (DPN) administration. We found that OVX produced strong and widespread changes of gene expression in both femoral bone and bone marrow. In the bone out of 22 genes, 20 genes were up- and 2 were downregulated after OVX. It is noteworthy that DPN restored mRNA expression of 10 OVX-induced changes (Aldh2, Col1a1, Daam1, Fgf12, Igf1, Il6r, Nfkb1, Notch1, Notch2 and Psen1) suggesting a modulatory role of ERβ in bone physiology. In bone marrow, out of 37 categorized genes, transcription of 25 genes were up- and 12 were downregulated indicating that the marrow is highly responsive to gonadal hormones. DPN modestly affected transcription, only expression of two genes (Nfatc1 and Tgfb1) was restored by DPN action. The PI3K/Akt signaling pathway was the most affected gene cluster following the interventions in bone and bone marrow, as demonstrated by canonical variates analysis (CVA). We suggested that our results contribute to a deeper understanding of alterations in gene expression of bone and bone marrow niche elicited by ERβ and selective ERβ analogs