Gorlin-Goltz syndrome : Clinicopathologic aspects

Gorlin-Goltz syndrome, also known as nevoid basal cell carcicoma syndrome, comes into being due to a genetic alteration produced by a mutation in the ?Patched? tumour suppressor gene, and it is inherited in a dominant autosomal way, though sporadic cases have been found. This syndrome shows a high penetrance and variable expressiveness. It is about a multisystemic process that is characterised by the presence of multiple pigmented basocellular carcinomas, keratocysts in the jaws, palmar and/or plantar pits and calcification of the falxcerebri. Together with these major features a great number of processes considered as minor features have also been described. The latter include numerous skeletical, dermatology related and neurological anomalies among others. In some occasions, the presence of very aggressive basocellular carcinomas has been described as well as other malignant neoplasias. Due to the importance of oral maxillofacial manifestations of this syndrome, it is fundamental to know its characteristic in order to make a diagnosis, an early preventive treatment and establish right genetic advice. In this work the main clinicopathologic and the therapeutic aspects related to the syndrome under consideration have been revised and updated

Aplicaciones de la citologia oral por raspado (exfoliativa) en el cáncer y precáncer oral

La citología por raspado es un procedimiento simple e incruento que ha sido objeto de controversia sobre su validez real en patología oral. En los últimos tiempos ha resurgido en base a su aplicación en el precáncer y el cáncer oral, tanto como metodología diagnóstica como predictiva y para la monitorización de los pacientes. Se han desarrollado nuevas técnicas sobre aspectos diagnósticos, como la aplicación 'brush biopsy', y múltiples estudios moleculares sobre las células recogidas. En esta revisión analizamos los aspectos más novedosos en relación con las aplicaciones de la citología por raspado o exfoliativa en la patología oral cancerosa y precancerosa, dirigida de un modo especial a los estudios moleculares y sus implicaciones diagnósticas y pronósticas.Scraped (exfoliative) cytology is a simple and harmless procedure, which has been a controversial technique according to its real validity in oral pathology. Lately it has re-emerged due to its application in oral precancer and cancer as a diagnostic and predictive method as well as for monitoring patients. New diagnostic techniques have been developed, such as 'brush biopsy' and multiple molecular studies using the cells collected. In this review we are going to analyse the more novel aspects related with the applications of the scraped or exfoliative cytology in oral precancerous and cancerous pathology, specially focusing on molecular studies and their diagnostic and prognostic implications

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Simple SummaryUveal melanoma (UM) is a rare aggressive eye cancer. Although treatment of the eye tumour is successful, about 50% of UM patients develop a relapse of their cancer in the liver. At present, such advanced disease is not curable. A better understanding of the metastatic UM (mUM) in the liver is essential to improve patient survival. This study examines both the response of immune cells within the liver to the UM secondaries (metastases), as well as the expression of various proteins by the UM cells. Our study demonstrates that there is a limited immune response to the mUM, but reveals that a certain type of reactive immune cell: a protumourigenic subset of macrophage is dominant within the mUM. Our research also reveals novel proteins within the mUM, which are specific to these cells and therefore may be targetable in future therapies.Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an "immunoscore" (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions

Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis

Background Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still unclear. Methods Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs. Cross-validation of the selected targets was achieved in 850 NSCLC tumours from TCGA datasets. Results Twelve targets were successfully validated by qPCR (upregulated: FEZF1-AS1, LINC01214, LINC00673, PCAT6, NUTM2A-AS1, LINC01929; downregulated: PCAT19, FENDRR, SVIL-AS1, LANCL1-AS1, ADAMTS9-AS2 and LINC00968). All of them were successfully cross-validated in the TCGA datasets. Abnormal DNA methylation was observed in the promoters of FENDRR, FEZF1-AS1, and SVIL-AS1. FEZF1-AS1 and LINC01929 were associated with survival in the TCGA set. Conclusions Our study provides through multiple levels of internal and external validation, a comprehensive list of dysregulated lncRNAs in NSCLC. We therefore envisage this dataset to serve as an important source for the lung cancer research community assisting future investigations on the involvement of lncRNAs in the pathogenesis of the disease and providing novel biomarkers for diagnosis, prognosis and therapeutic stratification

DNA methylation epigenotypes in breast cancer molecular subtypes

12 páginas, 3 figuras, 3 tablas.-- et al.[Introduction]: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and only a limited understanding exists of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. [Methods]: By using a microarray approach, we analyzed DNA methylation in regulatory regions of 806 cancer-related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biologic validation by pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A, and 48 luminal B paired breast cancer/adjacent tissues. With the all-subset selection method, we identified the most subtype-predictive methylation profiles in multivariable logistic regression analysis. [Results]: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. [Conclusions]: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.This work was supported by grants from project CGL2008-01131 (Departamento de Sanidad del Gobierno Vasco), S-PE08UN45 and PE09BF02 (Departamento de Ciencia y Tecnologia del Gobierno Vasco), BIO2008-04212, and RD06/0020/1019 (Red Tematica de Investigacion Cooperativa en Cancer, RTICC) from the MICINN. The CIBER de Enfermedades Raras is an initiative of the ISCIII. NGB had a doctoral fellowship from the Basque Government (Departamento de Educacion, Universidades e Investigacion).Peer reviewe

Piloting a Deep Learning Model for Predicting Nuclear BAP1 Immunohistochemical Expression of Uveal Melanoma from Hematoxylin-and-Eosin Sections

Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Monosomy 3 and BAP1 mutation are strong prognostic factors predicting metastatic risk in UM. Nuclear BAP1 (nBAP1) expression is a close immunohistochemical surrogate for both genetic alterations. Not all laboratories perform routine BAP1 immunohistochemistry or genetic testing, and rely mainly on clinical information and anatomic/morphologic analyses for UM prognostication. The purpose of our study was to pilot deep learning (DL) techniques to predict nBAP1 expression on whole slide images (WSIs) of hematoxylin and eosin (H&E) stained UM sections. Methods: One hundred forty H&E-stained UMs were scanned at 40 × magnification, using commercially available WSI image scanners. The training cohort comprised 66 BAP1+ and 74 BAP1− UM, with known chromosome 3 status and clinical outcomes. Nonoverlapping areas of three different dimensions (512 × 512, 1024 × 1024, and 2048 × 2048 pixels) for comparison were extracted from tumor regions in each WSI, and were resized to 256 × 256 pixels. Deep convolutional neural networks (Resnet18 pre-trained on Imagenet) and auto-encoder-decoders (U-Net) were trained to predict nBAP1 expression of these patches. Trained models were tested on the patches cropped from a test cohort of WSIs of 16 BAP1+ and 28 BAP1− UM cases. Results: The trained model with best performance achieved area under the curve values of 0.90 for patches and 0.93 for slides on the test set. Conclusions: Our results show the effectiveness of DL for predicting nBAP1 expression in UM on the basis of H&E sections only. Translational Relevance: Our pilot demonstrates a high capacity of artificial intelligence-related techniques for automated prediction on the basis of histomorphology, and may be translatable into routine histology laboratories