RESUMO
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/ß-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
Assuntos
Carcinoma/genética , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , Proteoma/genética , Transcriptoma , Acetilação , Animais , Antígenos de Neoplasias/genética , Carcinoma/imunologia , Carcinoma/patologia , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal/genética , Retroalimentação Fisiológica , Feminino , Instabilidade Genômica , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Repetições de Microssatélites , Fosforilação , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , Transdução de SinaisRESUMO
Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and we highlight the general principles of metastasis that have begun to emerge.
Assuntos
Carcinoma/patologia , Metástase Neoplásica/patologia , Animais , Plaquetas/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Movimento Celular , Transição Epitelial-Mesenquimal , Humanos , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Neutrófilos/metabolismo , Linfócitos T/imunologia , Microambiente TumoralRESUMO
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma/genética , Predisposição Genética para Doença , Inflamassomos/metabolismo , Ceratose/genética , Neoplasias Cutâneas/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose/química , Carcinoma/patologia , Cromossomos Humanos Par 17/genética , Epiderme/patologia , Mutação em Linhagem Germinativa , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Inflamassomos/genética , Interleucina-1/metabolismo , Ceratose/patologia , Proteínas NLR , Comunicação Parácrina , Linhagem , Domínios Proteicos , Pirina/química , Transdução de Sinais , Neoplasias Cutâneas/patologia , SíndromeRESUMO
Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.
Assuntos
Carcinoma/imunologia , RNA Longo não Codificante/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Evasão Tumoral/genética , Animais , Apoptose/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/patologia , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Longo não Codificante/genéticaRESUMO
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
Assuntos
Carcinoma/genética , Mutação , Neoplasias da Glândula Tireoide/genética , Carcinoma/patologia , Carcinoma Papilar , Variações do Número de Cópias de DNA , Fusão Gênica , Humanos , Câncer Papilífero da Tireoide , Glândula Tireoide/citologia , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
We identified a progenitor cell population highly enriched in samples from invasive and chemo-resistant carcinomas, characterized by a well-defined multigene signature including APOD, DCN, and LUM. This cell population has previously been labeled as consisting of inflammatory cancer-associated fibroblasts (iCAFs). The same signature characterizes naturally occurring fibro-adipogenic progenitors (FAPs) as well as stromal cells abundant in normal adipose tissue. Our analysis of human gene expression databases provides evidence that adipose stromal cells (ASCs) are recruited by tumors and undergo differentiation into CAFs during cancer progression to invasive and chemotherapy-resistant stages.
Assuntos
Adipogenia , Humanos , Animais , Carcinoma/patologia , Carcinoma/genética , Carcinoma/metabolismo , Células-Tronco/patologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/patologia , Neoplasias/patologia , Neoplasias/genéticaRESUMO
The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.
Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
Cell surface receptors play crucial roles in cellular responses to extracellular ligands, helping to modulate the functions of a cell based on information coming from outside the cell. Syndecan refers to a family of cell adhesion receptors that regulate both extracellular and cytosolic events. Alteration of syndecan expression disrupts regulatory mechanisms in a cell type-specific fashion, often leading to serious diseases, notably cancer. Given the multifaceted functions and distinct tissue distributions of syndecan, it will be important to unravel the gene-level intricacies of syndecan expression and thereby further understand its involvement in various carcinogenic processes. Although accumulating evidence indicates that the protein expression patterns of syndecan family members are significantly altered in cancer cells, the underlying gene-level mechanisms remain largely unknown. This review endeavors to explore syndecan gene expression levels across different cancer types by scrutinizing extensive cancer genome datasets using tools such as cBioPortal. Our analysis unveils that somatic mutations in SDC genes are rare occurrences, whereas copy number alterations are frequently observed across diverse cancers, particularly in SDC2 and SDC4. Notably, amplifications of SDC2 and SDC4 correlate with heightened metastatic potential and dismal prognosis. This underscores the recurrent nature of SDC2 and SDC4 amplifications during carcinogenesis and sheds light on their role in promoting cancer activity through augmented protein expression. The identification of these amplifications not only enriches our understanding of carcinogenic mechanisms but also hints at the potential therapeutic avenue of targeting SDC2 and SDC4 to curb cancer cell proliferation and metastasis.
Assuntos
Amplificação de Genes , Humanos , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Animais , Sindecana-4/genética , Sindecana-4/metabolismo , Sindecanas/genética , Sindecanas/metabolismo , Carcinoma/genética , Carcinoma/patologia , Carcinoma/metabolismo , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
INTRODUCTION: Pseudogenes have been implicated for their role in regulating cellular differentiation and organismal development. However, their role in promoting cancer-associated differentiation has not been well-studied. This study explores the tumour landscape of oesophageal carcinoma to identify pseudogenes that may regulate events of differentiation to promote oncogenic transformation. MATERIALS AND METHOD: De-regulated differentiation-associated pseudogenes were identified using DeSeq2 followed by 'InteractiVenn' analysis to identify their expression pattern. Gene expression dependent and independent enrichment analyses were performed with GSEA and ShinyGO, respectively, followed by quantification of cellular reprogramming, extent of differentiation and pleiotropy using three unique metrics. Stage-specific gene regulatory networks using Bayesian Network Splitting Average were generated, followed by network topology analysis. MEME, STREME and Tomtom were employed to identify transcription factors and miRNAs that play a regulatory role downstream of pseudogenes to initiate cellular reprogramming and further promote oncogenic transformation. The patient samples were stratified based on the expression pattern of pseudogenes, followed by GSEA, mutation analysis and survival analysis using GSEA, MAF and 'survminer', respectively. RESULTS: Pseudogenes display a unique stage-wise expression pattern that characterizes stage II (SII) ESCA with a high rate of cellular reprogramming, degree of differentiation and pleiotropy. Gene regulatory network and associated topology indicate high robustness, thus validating high pleiotropy observed for SII. Pseudogene-regulated expression of SOX2, FEV, PRRX1 and TFAP2A in SII may modulate cellular reprogramming and promote oncogenesis. Additionally, patient stratification-based mutational analysis in SII signifies APOBEC3A (A3A) as a potential hallmark of homeostatic mutational events of reprogrammed cells which in addition to de-regulated APOBEC3G leads to distinct events of hypermutations. Further enrichment analysis for both cohorts revealed the critical role of combinatorial expression of pseudogenes in cellular reprogramming. Finally, survival analysis reveals distinct genes that promote poor prognosis in SII ESCA and patient-stratified cohorts, thus providing valuable prognostic bio-markers along with markers of differentiation and oncogenesis for distinct landscapes of pseudogene expression. CONCLUSION: Pseudogenes associated with the events of differentiation potentially aid in the initiation of cellular reprogramming to facilitate oncogenic transformation, especially during SII ESCA. Despite a better overall survival of SII, patient stratification reveals combinatorial de-regulation of pseudogenes as a notable marker for a high degree of cellular differentiation with a unique mutational landscape.
Assuntos
Carcinoma , Citidina Desaminase , Neoplasias Esofágicas , Proteínas , Humanos , Pseudogenes , Teorema de Bayes , Carcinogênese/genética , Neoplasias Esofágicas/genética , Reprogramação Celular , Carcinoma/genética , Proteínas de Homeodomínio/genéticaRESUMO
AIMS: While epithelioid trophoblastic tumour (ETT) primarily arises from the uterus, cases have been increasingly documented at extrauterine sites, originating from an ectopic gestation or presenting as a metastatic tumour, leading to the major differential diagnosis of somatic carcinoma with trophoblastic differentiation. The precise separation of a gestational trophoblastic tumour from its somatic carcinoma mimics is highly relevant and crucial for patient management and prognosis. METHODS AND RESULTS: We summarise the clinicopathological and molecular features of four challenging epithelioid malignancies presenting at extrauterine sites, with ETT as the main differential diagnosis. All four tumours demonstrated histological and immunohistochemical features overlapping between a somatic carcinoma and an ETT, combined with inconclusive clinical and imaging findings. Serum beta-hCG elevation was documented in two cases. Short tandem repeat (STR) genotyping was performed and was informative in all cases. The presence of a unique paternal allelic pattern in the tumour tissue confirmed the diagnosis of ETT in two cases with an initial consideration of either somatic carcinoma or suspicion of a gestational trophoblastic tumour. The presence of matching genetic profile with the patient's paired normal tissue was seen in two other cases (both initially considered as ETT), confirming their somatic origin, including one metastatic triple-negative breast carcinoma and one primary lung carcinoma. CONCLUSIONS: Diagnostic separation of ETT at an extrauterine site from its somatic carcinoma mimics can be difficult at the histological and immunohistochemical levels. STR genotyping offers a robust ancillary tool that precisely separates ETT from somatic carcinomas with trophoblastic differentiation.
Assuntos
Carcinoma , Doença Trofoblástica Gestacional , Neoplasias Uterinas , Gravidez , Feminino , Humanos , Genótipo , Doença Trofoblástica Gestacional/diagnóstico , Doença Trofoblástica Gestacional/genética , Doença Trofoblástica Gestacional/patologia , Carcinoma/genética , Útero/patologia , Repetições de Microssatélites , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologiaRESUMO
AIMS: Salivary gland neoplasms (SGN) exhibiting the HMGA2::WIF1 fusion are recognized by their resemblance to histology found in canalicular adenoma. Recently, ~20% of cases among 28 HMGA2::WIF1-rearranged-SGN showed malignancy and adverse outcomes (recurrence, distant metastasis, and disease-specific mortality). Among them, MDM2/CDK4 amplifications were identified in one case. This outcome suggests that the MDM2/CDK4 amplifications could be useful to predict an aggressive course of carcinoma ex-pleomorphic adenoma (CEPA). METHODS AND RESULTS: We investigated the correlation between HMGA2 fusion and MDM2 amplification in four salivary gland neoplasms, providing detailed clinicopathological features and outcomes. Cases were selected from different institutions. Histological examination, immunohistochemistry, fluorescence in situ hybridization (FISH), RNA sequencing, and whole-exome capture were performed. The cohort included four CEPA cases, all female, aged between 32 and 89 years. Tumours arose from the parotid gland with an average size of 24.5 mm. None exhibited recurrence or distant metastases during the 4-5 months of follow-up. Pathologically, all cases displayed a peculiar atypical nuclei with 'gear-like appearance'. Immunohistochemically, tumours exhibited a biphasic pattern with myoepithelial and ductal differentiation markers. All cases showed HMGA2 overexpression and MDM2 amplification by FISH and RNA sequencing. In a control cohort of MDM2 nonamplified CEPA cases, not exhibiting the peculiar nuclear atypia. CONCLUSIONS: Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications.
Assuntos
Adenoma Pleomorfo , Amplificação de Genes , Proteína HMGA2 , Proteínas Proto-Oncogênicas c-mdm2 , Neoplasias das Glândulas Salivares , Humanos , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Feminino , Proteínas Proto-Oncogênicas c-mdm2/genética , Adulto , Pessoa de Meia-Idade , Idoso , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/patologia , Idoso de 80 Anos ou mais , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Carcinoma/genética , Carcinoma/patologia , Carcinoma/diagnóstico , Biomarcadores Tumorais/genética , Hibridização in Situ FluorescenteRESUMO
BACKGROUND: It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types. OBJECTIVE: The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens. METHODS: The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique. RESULTS: MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (Pâ=â0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (Pâ=â0.009) and CRA cases (Pâ=â0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (Pâ=â0.050) and perineural invasion (Pâ=â0.017). CONCLUSIONS: Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.
Assuntos
Adenoma , Neoplasias Colorretais , Forminas , MAP Quinase Quinase 1 , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Forminas/genética , Forminas/metabolismo , Adenoma/patologia , Adenoma/genética , Adenoma/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , Adulto , Imuno-Histoquímica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma/patologia , Carcinoma/genética , Carcinoma/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Copy-number alterations (CNAs) are a hallmark of cancer and can regulate cancer cell states via altered gene expression values. Herein, we have developed a copy-number impact (CNI) analysis method that quantifies the degree to which a gene expression value is impacted by CNAs and leveraged this analysis at the pathway level. Our results show that a high CNA is not necessarily reflected at the gene expression level, and our method is capable of detecting genes and pathways whose activity is strongly influenced by CNAs. Furthermore, the CNI analysis enables unbiased categorization of CNA categories, such as deletions and amplifications. We identified six CNI-driven pathways associated with poor treatment response in ovarian high-grade serous carcinoma (HGSC), which we found to be the most CNA-driven cancer across 14 cancer types. The key driver in most of these pathways was amplified wild-type KRAS, which we validated functionally using CRISPR modulation. Our results suggest that wild-type KRAS amplification is a driver of chemotherapy resistance in HGSC and may serve as a potential treatment target.
Assuntos
Carcinoma , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Genoma , Variações do Número de Cópias de DNA , Carcinoma/genética , Expressão GênicaRESUMO
SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.
Assuntos
Adenossarcoma , DNA Helicases , Proteínas Nucleares , Fatores de Transcrição , Neoplasias Uterinas , Humanos , Feminino , DNA Helicases/genética , DNA Helicases/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/deficiência , Proteínas Nucleares/genética , Proteínas Nucleares/deficiência , Adulto , Adenossarcoma/patologia , Adenossarcoma/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/genética , Imuno-Histoquímica , Carcinoma/patologia , Carcinoma/genéticaRESUMO
HER2 status is now routinely assessed in endometrial serous carcinoma (ESC) due to the reported predictive value of HER2 protein overexpression and/or gene amplification. Herein the authors compare 2 proposed testing and interpretation guidelines for HER2 in ESC. Forty-three consecutive cases of ESC that had been dually tested by both HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were interpreted using 2 sets of guidelines. Guideline set 1 (GS1) is the 2018 American Society of Clinical Oncology/College of American Pathologists guidelines for breast cancer. Guideline set 2 (GS2) is a recent proposal that is a slight modification of the enrollment criteria for the clinical trial (NCT01367002) that demonstrated a survival benefit for anti-HER2 therapy in ESC. By IHC, GS1 and GS2, respectively classified 39.5% (17/43) and 28% (12/43) of ESC as HER2-negative, 37.2% (16/43) and 53.4% (23/43) as HER2 equivocal, and 23.2% (10/43) and 18.6% (8/43) as HER2-positive ( P > 0.05 for all). IHC and FISH were highly concordant at the extremes using either set of guidelines, as no cases were found to be IHC3+/FISH-negative or IHC 0-1+/FISH-positive. GS1 and GS2 were comparable regarding the proportion of IHC equivocal cases that were HER2 amplified by FISH (19% vs 23% respectively; [ P = 0.71]). GS1 and GS2 displayed 98% (42/43) concordance regarding the final (IHC and/or FISH-based) classification of tumors as being HER2-positive or negative, and the same 13 cases were ultimately classified as HER2 amplified using either GS1 or GS2. One "discordant" case was classified as HER2-positive using GS2 but HER2-negative using GS1 (HER2 IHC score 2+ using both guidelines, HER2:CEP17 signal ratio of 3, HER2 signal number of 3.4). Six (14%) of the 43 cases (FISH Groups: 2, 3, and 4) would require IHC results to interpret the FISH findings using GS1. Because GS1 requires that the HER2 IHC staining be observed within a homogeneous and contiguous invasive cell population, and this is not a requirement in GS2, GS2 may be better suited for ESC given its frequently heterogeneous staining pattern. Additional studies may be required on the optimal interpretation of problematic dual-probe FISH scenarios in GS2 and the necessity for IHC correlation in such scenarios. Using either set of guidelines, our findings support a reflex testing strategy of restricting FISH testing to cases that are IHC equivocal.
Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias do Endométrio , Feminino , Humanos , Receptor ErbB-2/metabolismo , Hibridização in Situ Fluorescente/métodos , Neoplasias da Mama/patologia , Amplificação de Genes , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Carcinoma/genética , Biomarcadores Tumorais/metabolismoRESUMO
Epstein-Barr virus (EBV) is one of the major drivers of gastric carcinogenesis. EBV infection is established before tumour initiation and is generally maintained throughout tumour development; however, the significance of EBV in tumour maintenance and progression remains to be elucidated. Here, we report eight cases of EBV-associated gastric carcinoma (EBVaGC) with intratumoural heterogenous expression of EBV-encoded small RNA (EBER), a highly expressed latent gene of EBV, and demonstrate clinicopathological characteristics of these rare cases. By performing detailed histological assessment of EBER-positive and -negative components of each case, detection of EBV genome in tumour cells by fluorescence in situ hybridisation, TP73 methylation analysis, whole exome sequencing, and targeted gene panel sequencing, we identified tumours in two patients to be collision tumours of different origins. In the other six patients, some genetic/epigenetic alterations were shared between EBER-positive and -negative components, suggesting that EBV was eliminated from tumour cells during progression. Interestingly, in both tumour types, programmed death ligand 1 and intratumoural infiltration of CD8+ T lymphocytes were lower in EBER-negative than in EBER-positive components, suggesting an immunogenic role of EBV. To the best of our knowledge, this study is the first to demonstrate the detailed histological features and genetic/epigenetic alterations in EBVaGC with heterogenous EBER expression; the loss of EBV may benefit tumour progression and immune evasion and might be clinically important for selecting treatment strategies for such cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Genoma Viral , Carcinoma/genética , RNA Viral/genética , Microambiente TumoralRESUMO
The association between the cuproptosis-related genes and the immune infiltration and their prognostic value in thyroid carcinoma is still unexplored. Bioinformatics analyses were performed with data obtained from the TCGA dataset. The aberrantly expressed genes were selected. KEGG and GO analyses were conducted to explore the enriched pathways of the up-regulated or down-regulated genes in thyroid carcinoma. Totally 1495 genes were differentially expressed (691 up-regulated, 804 down-regulated) in thyroid carcinoma (p<0.05). The 10 cuproptosis-related RNAs (DLD, LIAS, LIPT1, FDX1, DLAT, MTF1, PDHA1, CDKN2A, GLS and PDHB) were also demonstrated to be aberrantly expressed in thyroid carcinoma patients tissues. FDX1 expression was correlated with the overall survival in thyroid carcinoma patients (HR=0.4995, 95% CI: 0.2688-0.9285, p=0.0282). Further multivariate cox regression analysis revealed that DLD (HR=24.8869, 95% CI: 4.48772-138.01181, p=0.00024), and LIAS (HR=7.74092, 95% CI: 1.12194-53.40898, p=0.03783) were associated with the survival of thyroid carcinoma patients. The immune infiltration analysis demonstrated that significant correlation between the 10 cuproptosis-related genes and immune infiltration in thyroid carcinoma (p<0.01). We presented the expression profiles of dysregulated genes in thyroid carcinoma. The findings of our study highlighted the potential of cuproptosis-related genes as prognostic biomarkers for thyroid carcinoma.
Assuntos
Apoptose , Biomarcadores Tumorais , Carcinoma , Cobre , Neoplasias da Glândula Tireoide , Transcriptoma , Humanos , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/terapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/terapia , Prognóstico , Biomarcadores Tumorais/análise , Fatores de Risco , Análise de Sequência de RNA , Transdução de SinaisRESUMO
Nuclear protein in testis (NUT) carcinoma, molecularly defined by the NUTM1 gene rearrangement, is most commonly reported in young adults in the sinonasal tract, nasopharynx, or thorax. At these sites, NUT carcinoma is an extremely aggressive malignancy with dismal prognosis. Recently, five cases of primary cutaneous NUT adnexal carcinoma have been reported with BRD3 and NSD3 fusion partners. Although NUT adnexal carcinomas are shown to have metastatic potential, they may behave less aggressively than extracutaneous NUT carcinomas. We report a case of a 59-year-old man who underwent a biopsy of a 3-cm plantar mass, which showed BRD4::NUTM1 fusion. The tumor was a poorly differentiated dermal neoplasm showing cytologic atypia, large vesicular nuclei with prominent nucleoli, conspicuous mitotic activity, and foci of necrosis. Immunohistochemically, the tumor showed positivity for keratins, EMA, SOX10, and NUT, with patchy smooth muscle actin. Molecular testing revealed BRD4::NUTM1 rearrangement. With no alternative primary identified by imaging, a diagnosis of primary cutaneous NUT carcinoma was favored. We hope to contribute to the limited body of knowledge on this entity, with emphasis on recognition as well as studying and defining its prognostic differences from extracutaneous NUT carcinomas.
Assuntos
Proteínas Nucleares , Proteínas de Fusão Oncogênica , Neoplasias Cutâneas , Fatores de Transcrição , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Carcinoma/genética , Carcinoma/patologia , Carcinoma/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas que Contêm BromodomínioRESUMO
Gastric cancer is a common malignant tumor, and due to its insidious onset and limited screening methods, most patients are diagnosed with advanced disease and have a poor prognosis. The circRNA in exosomes has an essential role in cancer diagnosis and treatment. However, the part of hsa_circ_0014606 within exosomes in gastric cancer progression is unclear. Firstly, we extracted exosomes from the serum of gastric cancer patients and healthy individuals by ultracentrifugation and analyzed the expression of hsa_circ_0014606 in both exosomes; then knocked down hsa_circ_0014606 in vivo and in vitro, respectively, to observe its effect on the physiological function of gastric cancer cells; finally, we used bioinformatics to screen hsa_circ_0014606 targeting miRNAs and mRNAs, and experiments were performed to verify the interrelationship between the three. The results showed that the level of hsa_circ_0014606 in the serum exosomes of gastric cancer patients was significantly higher than that of the healthy population. The knockdown of hsa_circ_0014606 slowed the proliferation of gastric cancer cells, significantly reduced migration and invasion ability, accelerated apoptosis, and reduced tumor size in mice. In addition, the expression of hsa_circ_0014606 was negatively correlated with the expression of miR-514b-3p and positively correlated with the expression of heterogeneous nuclear ribonucleoprotein C (HNRNPC). In conclusion, hsa_circ_0014606 exerted a pro-cancer effect indirectly through miR-514b-3p targeting gene HNRNPC, and this study provides a new potential target for treating gastric cancer.
Assuntos
Carcinoma , Exossomos , MicroRNAs , Neoplasias Gástricas , Animais , Humanos , Camundongos , Carcinogênese/genética , Carcinoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Exossomos/genética , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Choroid plexus carcinomas (CPCs) are rare, aggressive grade 3 tumors of the central nervous system associated with Li-Fraumeni syndrome (LFS) in a notable percentage of cases due to TP53 germline mutations. Understanding the correlation between CPCs and LFS is crucial for tailored management strategies. However, distinguishing CPCs from benign choroid plexus papillomas (CPPs) remains challenging, relying largely on histologic features. This study aimed to explore the association between CPCs and LFS, emphasizing the impact of TP53 mutations on diagnosis, treatment, and clinical outcomes. MATERIALS AND METHODS: Scientific databases such as PubMed, Scopus, and Web of Science were systematically searched up to January 2024 using keywords related to CPCs, LFS, TP53 mutation, and central nervous system tumors. Selection criteria included studies investigating the link between CPCs and LFS, their management approaches, and genetic implications of TP53 mutations. Ten relevant studies were selected for analysis after screening titles, abstracts, and full-text articles. Data extraction focused on clinical, genetic, and management factors related to CPCs associated with LFS. RESULTS: The review highlighted the strong association (36%) between CPCs and LFS, primarily due to TP53 germline mutations. Studies emphasized the need for genetic testing in patients with CPCs, especially in pediatric cases, to identify LFS implications. Furthermore, the impact of TP53 mutations on treatment strategies was emphasized, recommending irradiation-sparing therapies due to inferior survival rates associated with radiotherapy in LFS patients with CPCs. Cases illustrated the challenges in diagnosing CPCs and the importance of immunohistochemistry and genetic testing for TP53 mutations. CONCLUSION: CPCs pose challenges in diagnosis and management, particularly in distinguishing them from benign tumors. The association with LFS, often due to TP53 germline mutations, underscores the importance of genetic testing for early detection and tailored treatment strategies. Irradiation-sparing therapies are recommended for LFS-associated CPCs to mitigate the risk of secondary malignancies. Comprehensive profiling of CPC patients, especially in pediatric cases, is crucial for early detection and management of potential secondary cancers associated with LFS.