Ruolo delle tecniche di sequenziamento di ultima generazione nella gestione del paziente con carcinoma tiroideo

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Thyroid: Papillary Carcinoma with inv(7)(q21q34)

Review on Thyroid: Papillary Carcinoma with inv(7)(q21q34), with data on clinics, and the genes involved

AKAP9 (A kinase (PRKA) anchor protein (yotiao) 9)

Review on AKAP9 (A kinase (PRKA) anchor protein (yotiao) 9), with data on DNA, on the protein encoded, and where the gene is implicated

A Comprehensive Atlas of Perineuronal Net Distribution and Colocalization with Parvalbumin in the Adult Mouse Brain

Perineuronal nets (PNNs) surround specific neurons in the brain and are involved in various forms of plasticity and clinical conditions. However, our understanding of the PNN role in these phenomena is limited by the lack of highly quantitative maps of PNN distribution and association with specific cell types. Here, we present a comprehensive atlas of Wisteria Floribunda Agglutinin (WFA) positive PNNs and colocalization with parvalbumin (PV) cells for over 600 regions of the adult mouse brain. Data analysis shows that PV expression is a good predictor of PNN aggregation. In the cortex, PNNs are dramatically enriched in layer 4 of all primary sensory areas in correlation with thalamocortical input density, and their distribution mirrors intracortical connectivity patterns. Gene expression analysis identifies many PNN correlated genes. Strikingly, PNN anticorrelated transcripts are enriched in synaptic plasticity genes, generalizing PNN role as circuit stability factors

Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencingin aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas

Analysis of alternative mechanisms of ret gene activation in familial and sporadic medullary thyroid carcinoma

Mutazioni attivanti, germinali o somatiche, del protoncogene RET sono presenti nel 95-98% dei carcinomi middollari della tiroide (MTC) ereditari e nel 50% di quelli in forma sporadica. I casi che non presentano mutazioni del gene RET sono tuttora “orfani” di alterazioni oncogenetiche. In questo studio si sono analizzate le alterazioni nel numero di copie del gene RET in un vasto numero di MTC sporadici ed ereditari al fine di identificare possibili meccanismi di attivazione di RET alternativi alla mutazione puntiforme. Per questo scopo, 66 campioni di MTC (12 ereditari e 54 sporadici) sono stati studiati per le mutazioni puntiformi e per le alterazioni del numero di copie del gene RET. Mutazioni puntiformi di RET sono state trovate in 12/12 (100%) MTC ereditari e in 23/54 (42.6%) MTC sporadici mentre gli esperimenti di Fluorescence in situ Hybridization (FISH) hanno identificato alterazioni del numero di copie del gene RET in 17/66 (25.8%) dei casi studiati. Una più alta prevalenza di queste alterazioni, principalmente aneuploidie del cromosoma 10, sono state osservate negli MTC sporadici che presentavano la mutazione puntiforme di RET rispetto a quelli non mutati (P<0.003). Nessuna differenza è stata osservata analizzando i diversi tipi di mutazione. Negli MTC ereditari, la prevalenza delle alterazioni del numero di copie di RET era più bassa se confrontata con quella degli MTC sporadici ed era rappresentata esclusivamente dall’amplificazione del gene RET. Nessun caso di monosomia del cromosoma 10 o di perdita di eterozigosità del gene RET è invece stata rilevata. Una associazione statisticamente significativa è stata trovata fra casi che presentavano alterazioni del numero di copie del gene RET e il peggior andamento clinico della malattia. Questi risultati suggeriscono l’esistenza di ruoli diversi espletati dalle alterazioni del numero di copie del gene RET in questi tumori: negli MTC sporadici la prevalenza dell’aneuploidia del cromosoma 10 potrebbe favorire l’insorgenza della mutazione puntiforme di RET mentre, nei casi ereditari, l’amplificazione del gene RET potrebbe favorire la capacità trasformante della mutazione germinale conferendo il tumore di una maggiore aggressività. Nonostante l’importanza di queste evidenze, i casi sporadici di MTC che non presentano la mutazione puntiforme del gene RET rimangono “orfani” di un evento genetico responsabile della loro trasformazione tumorale

Minireview: RET/PTC rearrangements and braf mutations in thyroid tumorigenesis

Thyroid papillary carcinoma is the most common type of endocrine cancer. It is frequently associated with genetic alterations leading to activation of the MAPK signaling pathway. The two most frequently affected genes, BRAF and RET, are activated by either point mutation or as a result of chromosomal rearrangement. These mutations are tumorigenic in thyroid follicular cells and correlate with specific phonotypical features and biological properties of papillary carcinomas, including tumor aggressiveness and response to radioiodine therapy. Molecular inhibitors that block RET/PTC or BRAF kinase activity have shown substantial therapeutic effects in the experimental systems and are currently being tested in clinical trial

Alterations of the BRAF gene in thyroid tumors

BRAF belongs to the RAF family of protein kinases that are important components of the MAPK signaling pathway mediating cell growth, differentiation and survival. Activating point mutation of the BRAF gene resulting in V600E (previously designated as V599E) is a common event in thyroid papillary carcinoma, being found in approx 40% of this tumor. It has strong association with classical papillary carcinoma and tall cell and possibly Warthin-like variants. This mutation also occurs in thyroid poorly differentiated and anaplastic carcinomas, usually those containing areas of papillary carcinoma. Alterations in the BRAF gene do not overlap with RAS mutations and RET/PTC rearrangement, indicating that activation of one of the effectors of the MAPK pathway is sufficient for papillary thyroid carcinogenesis. Recently, another mechanism of BRAF activation has been identified, which involves chromosome 7q inversion that results in the AKAP9-BRAF fusion. It is rare in sporadic papillary carcinomas and is more common in tumors associated with radiation exposure. Yet another mechanism of BRAF activation may involve copy number gain, which is seen in a significant portion of thyroid follicular tumors of both conventional and oncocytic (Hürthle cell) types

BRAF copy number gains in thyroid tumors detected by fluorescence in situ hybridization

Point mutation of the BRAF gene is a common genetic event in papillary thyroid carcinomas. More recently, it has been found that BRAF can also participate in chromosomal rearrangement. In this study, we explore yet another possible mechanism of BRAF alteration, which involves copy number gain. Using fluorescence in situ hybridization with BRAF specific and chromosome 7 centromeric probes, we studied 62 follicular thyroid tumors and 32 papillary carcinomas. We found that numerical changes in BRAF copy number were rare in papillary thyroid carcinomas, while they occurred in 16-45% of follicular tumors of conventional and oncocytic (Hürthle cell) types. They were due to amplification of the gene or gain of one or more copies of chromosome 7. Tetrasomy for chromosome 7 was overall the most common finding. The changes in BRAF copy number did not overlap with RAS mutations in follicular tumors. In a group of follicular carcinomas, tumors with BRAF copy number gain were significantly more often widely invasive (67%) compared to tumors with no copy number change (18%). By Western blotting, the tumors carrying four copies of the gene revealed higher expression of BRAF protein, suggesting that copy number gain may represent another mechanism of BRAF activation in thyroid tumors