19 research outputs found
Tumeurs mésenchymateuses utérines associées à des translocations : du nouveau sans oublier l’ancien. Une approche diagnostique intégrée
No full textCette revue se concentre sur les entités mésenchymateuses utérines présentant sur le plan moléculaire une altération unique, nécessaire et suffisante à la tumorigénèse et à la progression tumorale. L’ensemble de ces entités ont en commun ce que l’on nomme un profil génomique simple, terme recoupant l’absence de remaniements chromosomiques significatifs objectivables en CGH Array (délétions, gains, amplifications….) et un faible nombre de mutations (« low mutational burden »). Certaines de ces entités diagnostiques sont connues et bien décrites depuis longtemps en dehors de la sphère gynécologique. On peut s’interroger sur les raisons pour lesquelles la pathologie utérine mésenchymateuse accuse un certain retard par rapport à la pathologie des tissus mous extra gynécologique. Comment expliquer que les tumeurs myofibroblastiques inflammatoires font l’objet de riches descriptions cliniques et morphologiques depuis les années 70 tandis que les premières séries utérines ad hoc n’apparaissent qu’au début des années 2000 ? Les progrès exponentiels et la démocratisation des techniques de biologie moléculaire et de séquençage ARN expliquent en partie ce différentiel dans la mise au jour d’entités diagnostiques nouvelles. Il semble également que la prépondérance effective des lésions musculaires lisses et leurs grandes richesses morphologiques ait en partie occulté l’éventail des diagnostics différentiels envisagés en pathologie utérine. On peut par ailleurs supposer que la facilité à la fois en termes de geste technique, d’accessibilité et de prise de décision thérapeutique à la procédure d’hystérectomie a en partie tronqué nos connaissances sur le potentiel évolutif et l’histoire naturelle de ces lésions, guéries par le geste chirurgical. Ainsi en parcourant cette revue, le lecteur pourra constater que pour nombre d’entités la question de la terminologie « bénin vs malin » n’est pas tranchée et que les outils morphologiques et/ou moléculaires permettant une stratification pronostique fiable sont en cours d’évaluation et amenés à évoluer. Le manque de recul clinique pour beaucoup de ces entités récentes appelle à la prudence, passant par l’utilisation de la terminologie « potentiel de malignité indéterminé ». Ce manque de recul clinique illustre le retard à combler en pathologie mésenchymateuse utérine, retard qui ne pourra être rattrapé qu’en généralisant auprès des pathologistes la richesse du spectre diagnostique des lésions utérines et en déconstruisant l’idée d’une hégémonie des lésions musculaires lisses. Nous espérons que cette revue ne soit pas qu’un simple inventaire des nouvelles entités diagnostiques et moléculaires, mais permette également d’accroitre la vigilance de tout pathologiste amené à prendre en charge une lésion utérine et à lui donner les outils nécessaires pour élargir son spectre de diagnostics différentiels. C’est en améliorant en tant que communautés scientifiques nos connaissances que nous pourrons accumuler les données cliniques nécessaires à une meilleure caractérisation de ces lésions et donc à une prise en charge adéquate de ces patientes. L’enjeu thérapeutique sur le court terme est déjà appréciable à travers l’utilisation de thérapies ciblées. Par exemple les inhibiteurs de ALK dans les tumeurs myofibroblastiques inflammatoires, les inhibiteurs de tyrosine kinase dans les sarcomes COL1A::PDGFB réarrangés, les inhibiteurs de la voie mTOR ou MET dans les PEComes…Face au bouleversement des paradigmes diagnostiques apporté par la biologie moléculaire et particulièrement par le RNAseq, l’étape suivante sera de reclasser les nouvelles entités selon l’évolution clinique, les données intégrées morphologiques, immunohistochimiques et moléculaires. Une avancée majeure consistera dans l’identification de biomarqueurs immunohistochimiques qui permettront une approche diagnostique plus immédiate, sans les temps d’attente des techniques moléculaires, permettant une diffusion ubiquitaire dans les laboratoires de pathologie.[Translocation-associated uterine mesenchymal tumors: The new without forgetting the old. An integrated diagnostic approach]. This review focuses on uterine mesenchymal tumors that are defined on a molecular level by a single and unique genetic alteration, that is somehow necessary and sufficient to allow tumor growth and progression. Although diverse from a clinical, morphological and immunohistochemical point of view, the different entities we are going to talk about share both a simple genomic profile with a low number of chromosomal alterations observed by CGH Array (few deletions, gains or amplifications...) and a low mutational burden observed by sequencing technics. Some of these entities are already well known and described in the literature when found outside of the uterus and gynecological tract. It remains intriguing that uterine mesenchymal pathology has been lagging behind when compared to its extrauterine counterpart. How can we explain that when it comes to inflammatory myofibroblastic tumors, abundant numbers of articles have been published since the 70's, but it was only in the early 2000s that the first relevant descriptions of this tumor in the uterus emerged? Certainly, the increased accuracy, availability, and use of molecular biology technics and in particular RNA sequencing in the area of uterine pathology can partly explain the reduction of the gap between soft tissue and uterine pathology we currently observe. Other reasons explaining this gap may be the high prevalence of smooth muscle tumors in the uterus and the abounding diversity of their morphological aspects, which may have partly eclipsed the array of differential diagnoses. Last but not least, one can hypothesize that the relative "simplicity" of hysterectomy procedures, referring to their safety and accessibility, has cured most of the lesions and partly clouded our knowledge regarding the biological potential and natural history of these newly described entities. As a consequence of this situation, our reader will often encounter the wording "uncertain malignant potential", as for some of these rare entities, evidence to establish reliable prognostic variables is still insufficient. We hope this review to be a useful tool to guide pathologists through the diversity and complexity of uterine mesenchymal tumors. As a scientific and medical community, sharing this knowledge will help us to collectively raise our vigilance and awareness by expanding the array of our differential diagnoses. We hope this will lead to more cases being accurately diagnosed, and ultimately, to a deeper knowledge regarding the biological potential and clinical evolution of these tumors. From a therapeutical point of view, the consequences of an accurate diagnosis for the patient are already appreciable through the use of targeted therapy. Examples include: ALK inhibitors in inflammatory myofibroblastic tumor, tyrosine-kinase inhibitors in COL1A::PDGFB rearranged sarcomas or mTOR inhibitors in PEComa
High Level Mammographic Information Fusion For Real World Ontology Population
No full textInternational audienceIn this paper, we propose a novel approach for ontology instantiating from real data related to the mammographic domain. In our study, we are interested in handling two modalities of mammographic images: mammography and Breast MRI. Firstly, we propose to model both images content in ontological representations since ontologies allow the description of the objects from a common perspective. In order, to overcome the ambiguity problem of representation of image's entities, we propose to take advantage of the possibility theory applied to the ontological representation. Second, both local generated ontologies are merged in a unique formal representation with the use of two similarity measures: syntactic measure and possibilistic measure. The candidate instances are, finally, used for the global domain ontology populating in order to empower the mammographic knowledge base. The approach was validated on real world domain and the results were evaluated in terms of precision and recall by an expert. [ABSTRACT FROM AUTHOR
High Level Mammographic Information Fusion For Real World Ontology Population
No full textInternational audienceIn this paper, we propose a novel approach for ontology instantiating from real data related to the mammographic domain. In our study, we are interested in handling two modalities of mammographic images: mammography and Breast MRI. Firstly, we propose to model both images content in ontological representations since ontologies allow the description of the objects from a common perspective. In order, to overcome the ambiguity problem of representation of image's entities, we propose to take advantage of the possibility theory applied to the ontological representation. Second, both local generated ontologies are merged in a unique formal representation with the use of two similarity measures: syntactic measure and possibilistic measure. The candidate instances are, finally, used for the global domain ontology populating in order to empower the mammographic knowledge base. The approach was validated on real world domain and the results were evaluated in terms of precision and recall by an expert. [ABSTRACT FROM AUTHOR
Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction
No full textWorldwide, colorectal cancer (CRC) is a deadly disease whose death rate ranks second among cancers though its incidence ranks third. Early CRC detection is key and is associated with improved survival outcomes. However, existing tests for CRC diagnosis have several weaknesses thus rendering them inefficient. Moreover, reliable prognostic tests that can predict the overall cancer outcome and recurrence of the disease as well as predictive markers that can assess effectiveness of therapy are still lacking. Thus, shifting to noninvasive liquid biopsy or blood-based biomarkers is vital to improving CRC diagnosis, prognosis, and prediction. Methylated circulating tumor DNA (ctDNA) has gained increased attention as a type of liquid biopsy that is tumor-derived fragmented DNA with epigenetic alterations. Methylated ctDNA are more consistently present in blood of cancer patients as compared to mutated ctDNA. Hence, methylated ctDNA serves as a potential biomarker for CRC that is worth investigating. In this review, we explore what has been reported about methylated ctDNA as a biomarker for CRC diagnosis that can distinguish between CRC patients or those having adenoma and healthy controls as validated specifically through ROC curves. We also examine methylated ctDNA as a biomarker for CRC prognosis and prediction as confirmed through robust statistical analyses. Finally, we discuss the major technical challenges that limits the use of methylated ctDNA for clinical application and suggest possible recommendations to enhance its usage. © 2021, The Author(s)
Comprehensive Molecular Characterization of a Large Series of Calcified Chondroid Mesenchymal Neoplasms Widening Their Morphologic Spectrum
No full textInternational audienceRecently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5′ partners, including most frequently FGFR2 (14 cases), TEK or FGFR1 . Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions
A novel LARGE1-AFF2 fusion expanding the molecular alterations associated with the methylation class of neuroepithelial tumors with PATZ1 fusions
No full textInternational audienceA novel DNA methylation class of tumor within the central nervous system, the "neuroepithelial tumor (NET), PATZ1 fusion-positive" has recently been identified in the literature, characterized by EWSR1-and MN1-PATZ1 fusions. The cellular origin of this tumor type remains unknown, wavering between glioneuronal or mesenchymal (as round cell sarcomas with EWSR1-PATZ1 of the soft tissue). Because of the low number of reported cases, this tumor type will not be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS). Herein, we report one case of a CNS tumor classified by DNA methylation analysis as NET-PATZ1 but harboring a novel LARGE1-AFF2 fusion which has until now never been described in soft tissue or the CNS. We compare its clinical, histopathological, immunophenotypical, and genetic features with those previously described in NET-PATZ1. Interestingly, the current case presented histopathological (astroblastoma-like features, glioneuronal phenotype), clinical (with a favorable course), genetic (1p loss), and epigenetic (DNA-methylation profiling) similarities to previously reported cases of NET-PATZ1. Our results added data suggesting that different histomolecular tumor subtypes seem to be included within the methylation class "NET, PATZ1 fusion-positive", including non PATZ1 fusions, and that further cases are needed to better characterize them
A risk progression breast epithelial 3D culture model reveals Cx43/hsa_circ_0077755/miR-182 as a biomarker axis for heightened risk of breast cancer initiation
No full textmRNA-circRNA-miRNAs axes have been characterized in breast cancer, but not as risk-assessment axes for tumor initiation in early-onset breast cancer that is increasing drastically worldwide. To address this gap, we performed circular RNA (circRNA) microarrays and microRNA (miRNA) sequencing on acini of HMT-3522 S1 (S1) breast epithelial risk-progression culture model in 3D and chose an early-stage population miRNome for a validation cohort. Nontumorigenic S1 cells form fully polarized epithelium while pretumorigenic counterparts silenced for gap junction Cx43 (Cx43-KO-S1) lose epithelial polarity, multilayer and mimic premalignant in vivo mammary epithelial morphology. Here, 121 circRNAs and 65 miRNAs were significantly dysregulated in response to Cx43 silencing in cultured epithelia and 15 miRNAs from the patient cohort were involved in epithelial polarity disruption. Focusing on the possible sponging activity of the validated circRNAs to their target miRNAs, we found all miRNAs to be highly enriched in cancer-related pathways and cross-compared their dysregulation to actual miRNA datasets from the cultured epithelia and the patient validation cohort. We present the involvement of gap junction in post-transcriptional axes and reveal Cx43/hsa_circ_0077755/miR-182 as a potential biomarker signature axis for heightened-risk of breast cancer initiation, and that its dysregulation patterns might predict prognosis along breast cancer initiation and progression. © 2021, The Author(s)
Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair
No full textAbstract Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS
