RESUMEN
Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.
Asunto(s)
Carcinoma de Células Renales , Fumarato Hidratasa , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Persona de Mediana Edad , Femenino , Masculino , Adulto , Neoplasias Renales/genética , Neoplasias Renales/patología , Inmunohistoquímica , Anciano , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/patología , Mutación de Línea Germinal , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/deficiencia , Cisteína/análogos & derivados , Neoplasias Cutáneas , Neoplasias Uterinas , LeiomiomatosisRESUMEN
Lung cancer is the foremost cause of cancer related mortality among men and one of the most fatal cancers among women. Notably, the 5-year survival rate of lung cancer is very low; 5% in developing countries. This low survival rate can be attributed to factors like late stage diagnosis, rapid postoperative recurrences in the patients undergoing treatment and development of chemoresistance against different agents used for treating lung cancer. Therefore, in this study we evaluated the potential of a recently identified protein namely TIPE3 which is known as a transfer protein of lipid second messengers as a lung cancer biomarker. TIPE3 was found to be significantly upregulated in lung cancer tissues indicating its role in the positive regulation of lung cancer. Supporting this finding, knockout of TIPE3 was also found to reduce the proliferation, survival and migration of lung cancer cells and arrested the G2 phase of cell cycle through inactivation of Akt/mTOR, NF-κB, STAT-3 signaling. It is well evinced that tobacco is the major risk factor of lung cancer which affects both males and females. Therefore, this study also evaluated the involvement of TIPE3 in tobacco mediated lung carcinogenesis. Notably, this study shows for the first time that TIPE3 positively regulates tobacco induced proliferation, survival and migration of lung cancer through modulation of Akt/mTOR signaling. Thus, TIPE3 plays critical role in the pathogenesis of lung cancer and hence it can be specifically targeted to develop novel therapeutic strategies.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/deficiencia , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Técnicas de Inactivación de Genes/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Neoplasias Pulmonares/patología , FN-kappa B/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
AIMS: This study evaluated the association of mucinous metaplasia (MM) with tumor cell proliferation, androgen receptor (AR) expression and invasiveness in Pten conditional knockout mice and the prognostic value of MM markers for patients with PCa. MAIN METHODS: Prostatic lobes samples from genetic engineered mouse model Ptenf/f and Pb-Cre4/Ptenf/f were submitted for histopathological analysis and tissue expression of AR, the proliferation marker Ki67, alpha-smooth muscle actin, and laminin. RNAseq data of prostatic lobes samples were analyzed searching for MM gene expression patterns. We also investigated gene and protein expression related to MM in human PCa public databases. KEY FINDINGS: All knockout animals analyzed showed at least one area of stroma-invading MM, which was absent in the control animals. The tumoral regions of MM showed a proliferative index 5 times higher than other tumoral areas and low expression of the AR (less than 20% of the cells were AR-positive). Disrupted basement membrane areas were observed in MM. The mouse and human PCa transcriptomes exhibited increased expression of the MM markers such as MUC1, MUC19, MUC4, MUC5AC, MUC5B, and TFF3. Gene expression profile was associated with castration-resistant prostate cancer (CRPC) and with a lower probability of freedom from biochemical recurrence. SIGNIFICANCE: The expression of goblet cell genes, such as MUC1, MUC5AC, MUC5B, and TFF3 have significant prognostic value for PCa patients and represent another class of potential therapeutic targets.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/deficiencia , Mucinas/biosíntesis , Fosfohidrolasa PTEN/deficiencia , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Animales , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Metaplasia/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Mucinas/genética , Fosfohidrolasa PTEN/genética , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
Ancillary immunohistochemical tools can facilitate an integrated diagnosis of endometrial pathology. According to The Cancer Genome Atlas classification, endometrial cancers are of four molecular subtypes: mismatch repair (MMR)-deficient (MMR-d), p53 mutation (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP). As the specific histological and immunohistochemical features of POLEmut and NSMP subtypes are unknown, these cancers are categorized based on molecular analysis. In this study, we analyzed POLEmut-subtype endometrioid carcinoma (EC) using a custom-made cancer gene panel and the Catalog of Somatic Mutations in Cancer (COSMIC) database, extracted a characteristic genome profile, and identified an immunohistochemical marker that could be used as a diagnostic tool. The results indicated that the POLEmut-subtype EC exhibited nonsense mutations in the ataxia telangiectasia mutated (ATM) gene and a subsequent loss of ATM expression, which was monitored through immunohistochemical analysis. Moreover, analyses using the COSMIC database indicated that POLEmut-subtype EC cases often harbored similar ATM nonsense mutations. These results suggest that ATM expression is a potential immunohistochemical marker for the differential diagnosis of POLEmut- and NSMP-subtype EC. DATA AVAILABILITY: The data supporting the findings of this study are available upon request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Biomarcadores de Tumor/genética , Carcinoma Endometrioide/genética , Codón sin Sentido , ADN Polimerasa II/genética , Neoplasias Endometriales/genética , Inmunohistoquímica , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Biomarcadores de Tumor/deficiencia , Carcinoma Endometrioide/enzimología , Carcinoma Endometrioide/patología , Análisis Mutacional de ADN , Bases de Datos Genéticas , Diagnóstico Diferencial , Neoplasias Endometriales/enzimología , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , TranscriptomaRESUMEN
Superficial angiomyxomas (SAMs) are benign cutaneous tumors that arise de novo and in the setting of the Carney complex (CC), an autosomal dominant disease with several cutaneous manifestations including lentigines and pigmented epithelioid melanocytomas. Although most SAM do not pose a diagnostic challenge, a subset can demonstrate histopathologic overlap with other myxoid tumors that arise in the skin and subcutis. Traditional immunohistochemical markers are of limited utility when discriminating SAM from histopathologic mimics. Since protein kinase A regulatory subunit 1 alpha (PRKAR1A) genetic alterations underlie most CC cases, we investigated whether SAM demonstrate loss of PRKAR1A protein expression by immunohistochemistry. In our series, 29 SAM, 26 myxofibrosarcoma, 5 myxoid dermatofibrosarcoma protuberans, 11 superficial acral fibromyxomas, and 18 digital mucous cysts were characterized. Of the 29 SAM examined in this study, 1 was associated with documented CC in a 5-year-old girl. SAM tended to arise in adults (mean 49.7 y; range: 5 to 87 y). Loss of PRKAR1A was seen in 55.2% of cases (16/29) and had a male predilection (87.5%, 12/16). PRKAR1A-inactivated SAM demonstrated significant nuclear enlargement (100%, 16/16 vs. 23.1%, 3/13), multinucleation (81.3%, 13/16 vs. 23.1%, 3/13), and presence of neutrophils (43.8%, 7/16 vs. 0%, 0/13). In contrast, PRKAR1A was retained in all cases of myxofibrosarcoma (100%, 26/26), myxoid dermatofibrosarcoma protuberans (100%, 5/5), superficial acral fibromyxomas (100%, 11/11), and digital mucous cyst (100%, 18/18). Taken together, PRKAR1A loss by immunohistochemistry can be used as an adjunctive assay to support the diagnosis of SAM given the high specificity of this staining pattern compared with histopathologic mimics.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Complejo de Carney/enzimología , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/deficiencia , Quistes/enzimología , Dermatofibrosarcoma/enzimología , Fibroma/enzimología , Inmunohistoquímica , Mixoma/enzimología , Neoplasias Cutáneas/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Complejo de Carney/patología , Niño , Preescolar , Quistes/patología , Dermatofibrosarcoma/patología , Femenino , Fibroma/patología , Humanos , Masculino , Persona de Mediana Edad , Mixoma/patología , Valor Predictivo de las Pruebas , Neoplasias Cutáneas/patologíaRESUMEN
So-called primary yolk sac tumors of the vulva are very rare and often have an aggressive disease course. Their molecular features have not been previously characterized. There is also a well-documented group of SMARCB1 (INI-1)-deficient vulvar neoplasms, which includes proximal-type epithelioid sarcoma and myoepithelial carcinoma. Until now, "vulvar yolk sac tumors" and SMARCB1-deficient neoplasms were considered unrelated diseases. After reviewing an index case of a vulvar yolk sac tumor with loss of SMARCB1 by immunohistochemistry, we retrospectively identified 2 additional cases diagnosed as vulvar yolk sac tumors. Patient ages were 34, 32, and 25 years old, and 2 tumors were associated with a pregnancy. All 3 cases showed morphology typical of a yolk sac tumor, and by immunohistochemistry all were positive for SALL4, glypican-3, keratins, and lacked CD34 positivity. All tumors also demonstrated loss of SMARCB1 in tumor cells. Targeted molecular profiling was performed in 2 cases and identified 2 copy deletion of SMARCB1, without genomic alterations typically seen in gonadal yolk sac tumors. In the third case, isochromosome 12p was not identified by fluorescence in situ hybridization. All 3 patients had either local recurrences or distant metastases, and 2 died of disease. One patient had progressive disease while receiving the enhancer of zeste homolog 2 inhibitor tazemetostat. Overall, these findings suggest that vulvar tumors with pure yolk sac-like morphology may represent morphologic variants of SMARCB1-deficient tumors and not veritable germ cell neoplasia. This potential reclassification may have both prognostic and treatment implications and warrants study of additional extragonadal yolk sac tumors.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Tumor del Seno Endodérmico/química , Proteína SMARCB1/deficiencia , Neoplasias de la Vulva/química , Adulto , Biomarcadores de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Par 12 , Progresión de la Enfermedad , Tumor del Seno Endodérmico/genética , Tumor del Seno Endodérmico/secundario , Tumor del Seno Endodérmico/cirugía , Femenino , Eliminación de Gen , Humanos , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Proteína SMARCB1/genética , Resultado del Tratamiento , Neoplasias de la Vulva/genética , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugíaRESUMEN
Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum ß-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Mola Hidatiforme/química , Neoplasias Uterinas/química , Adulto , Biomarcadores de Tumor/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Humanos , Mola Hidatiforme/genética , Mola Hidatiforme/patología , Inmunohistoquímica , Técnicas de Diagnóstico Molecular , Sobrediagnóstico , Valor Predictivo de las Pruebas , Embarazo , Pronóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
Small cell carcinoma of hypercalcemic type (SCCOHT) is a rare gynaecological neoplasm, originating mostly in the ovaries. Cervical origin of this very aggressive malignancy with unknown histogenesis is an extremely rare condition, without published management recommendations. Alterations in SMARCA4 gene are supposed to play the major role in SCCOHT oncogenesis and their identification is crucial for the diagnosis. Adequate genetic counselling of the patients and their families seems to be of great importance. Optimal management and treatment approaches are not known yet but may extremely influence the prognosis of young female patients that suffer from this very resistant disease. Nowadays, a translational research seems to be the key for the further diagnostic and treatment strategies of SCCOHT. The purpose of the case report is to provide practical information and useful recommendations on the diagnosis, management, and treatment of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT.
Asunto(s)
Carcinoma de Células Pequeñas/metabolismo , ADN Helicasas/deficiencia , Hipercalcemia/metabolismo , Proteínas Nucleares/deficiencia , Factores de Transcripción/deficiencia , Neoplasias del Cuello Uterino/metabolismo , Adolescente , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Carcinoma de Células Pequeñas/diagnóstico , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/terapia , ADN Helicasas/genética , Resultado Fatal , Femenino , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Hipercalcemia/terapia , Mutación , Proteínas Nucleares/genética , Factores de Transcripción/genética , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapiaRESUMEN
Background: The expression of Fucosidase, alpha-L-2 (FUCA2) varies across tumors. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) is poorly defined. Methods: We analyzed profiles of FUCA2 expression using datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Next, gene alteration, clinical characteristics and prognostic values of FUCA2 were elucidated based on TCGA pan-cancer data. This was followed by gene set enrichment analysis by R software. Relationships between FUCA2 expression and immune infiltration and immune-related genes were also evaluated. Moreover, the association of immune cell infiltration with FUCA2 expression was evaluated across three different sources of immune cell infiltration data, namely the TIMER online, ImmuCellAI databases, as well as a published study. In addition, MTT assays was also conducted to validate the oncogene role of FUCA2 in lung cancer cells. Results: FUCA2 was upregulated in most tumors, and this was significantly associated with poor survival rates. Gene set enrichment analysis uncovered that FUCA2 correlated with immune pathways in different tumor types. FUCA2 expression was positively related to tumor associated macrophages (TAMs), especially M2-like TAMs. Moreover, FUCA2 level showed a positive relationship with most immunosuppression genes, including programmed death-ligand 1 (PD-L1), transforming growth factor beta 1 (TGFB1), and interleukin-10 (IL10) in most cancer types. FUCA2 knockdown inhibited the cell viability in lung cancer cells. Conclusions: Our study reveals that FUCA2 is a potential oncogene and is indicative biomarker of a worse prognosis in pan-cancer. High FUCA2 expression may contribute to increased infiltration of TAMs and associates with an immunosuppressive microenvironment, providing a potential target for tumor therapy.
Asunto(s)
Biomarcadores de Tumor/inmunología , Neoplasias Pulmonares/inmunología , alfa-L-Fucosidasa/inmunología , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Supervivencia Celular/inmunología , Humanos , Neoplasias Pulmonares/diagnóstico , Pronóstico , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología , alfa-L-Fucosidasa/deficiencia , alfa-L-Fucosidasa/genéticaRESUMEN
Mimickers of neuroendocrine neoplasms (NEN) include a number of important pitfall tumors. Here, we describe our experience with mesenchymal mimics of NENs to illustrate their spectrum and draw the attention particularly to a group of mesenchymal/non-epithelial neoplasms (MN) that combine epithelioid histology with neuroendocrine (NE-) features and peculiar genetic abnormalities. In a consultation series of 4498 cases collected between 2009 and 2021, 2099 neoplasms expressing synaptophysin and/or chromograninA were reviewed and analyzed. A total of 364 (18%) were diagnosed as non-NENs, while the remaining tumors were NEN. The group of mesenchymal/non-epithelial neoplasms with NE-features (MN-NE) included 31/364 (8%) cases. These mostly malignant neoplasms showed an epithelioid morphology. While all but one tumor expressed synaptophysin, mostly patchy, only 10/29 (34%) co-expressed chromograninA. A total of 13/31 (42%) of the MN-NE showed EWSR1-related gene fusions (6 Ewing sarcomas, 5 clear cell sarcomas, and 1 desmoplastic small round cell tumor, 1 neoplasm with FUS-CREM gene fusion) and 7 (23%) were SWI/SNF (SMARCB1 or SMARCA4)-deficient neoplasms. The remaining MN-NE included synovial sarcoma, sclerosing epithelioid mesenchymal neoplasm, melanoma, alveolar soft part sarcoma, solitary fibrous tumor, and chordoma. A total of 27/31 MN-NE were from the last 8 years, and 6 of them were located in the pancreas. Eleven MN-NE were initially diagnosed as neuroendocrine carcinomas (NECs). MN-NE with epithelioid features play an increasing role as mimickers of NECs. They mostly belong to tumors with gene fusions involving the EWSR1 gene, or with SWI/SNF complex deficiency. Synaptophysin expression is mostly patchy and chromograninA expression is infrequent in MN-NE of this series and data extracted from literature.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Carcinoma Neuroendocrino/genética , ADN Helicasas/deficiencia , Fusión Génica , Neoplasias de Tejido Conjuntivo/genética , Proteínas Nucleares/deficiencia , Proteína EWS de Unión a ARN/genética , Proteína SMARCB1/deficiencia , Factores de Transcripción/deficiencia , Carcinoma Neuroendocrino/química , Carcinoma Neuroendocrino/patología , Cromogranina A/análisis , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Técnicas de Apoyo para la Decisión , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Neoplasias de Tejido Conjuntivo/química , Neoplasias de Tejido Conjuntivo/patología , Valor Predictivo de las Pruebas , Proteína FUS de Unión a ARN/genética , Sinaptofisina/análisisRESUMEN
BACKGROUND: Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex-deficiency have been described. CASE PRESENTATION: A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene. CONCLUSIONS: We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2.
Asunto(s)
Biomarcadores de Tumor , Proteínas Cromosómicas no Histona/deficiencia , ADN Polimerasa II/genética , Neoplasias de la Vesícula Biliar/patología , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Tumor Rabdoide/patología , Factores de Transcripción/deficiencia , Adulto , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Diferenciación Celular , Análisis Mutacional de ADN , Proteínas de Unión al ADN/deficiencia , Resultado Fatal , Femenino , Neoplasias de la Vesícula Biliar/química , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/cirugía , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Fenotipo , Tumor Rabdoide/química , Tumor Rabdoide/genética , Tumor Rabdoide/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Malignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney. CASE PRESENTATION: A 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3-4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor. CONCLUSION: While it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Papilar/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Amplificación de Genes , Neoplasias Renales/genética , Trasplante de Riñón/efectos adversos , Telomerasa/genética , Biomarcadores de Tumor/deficiencia , Carcinoma Papilar/etiología , Carcinoma Papilar/secundario , Carcinoma Papilar/terapia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Renales/etiología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo , Resultado del Tratamiento , Urotelio/patologíaRESUMEN
Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA-IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40-10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P = 1.2 × 10-10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.
Asunto(s)
Biomarcadores de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Y/genética , Histona Demetilasas/genética , Neoplasias Pulmonares/genética , Antígenos de Histocompatibilidad Menor/genética , Adulto , Anciano , Biomarcadores de Tumor/deficiencia , Metilación de ADN , Conjuntos de Datos como Asunto , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Disparidades en el Estado de Salud , Histona Demetilasas/deficiencia , Humanos , Estimación de Kaplan-Meier , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neumonectomía , Pronóstico , Medición de Riesgo/estadística & datos numéricos , Factores Sexuales , Secuenciación del ExomaRESUMEN
PURPOSE: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. METHODS: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method. RESULTS: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0). CONCLUSIONS: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor/genética , Fumarato Hidratasa/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Inhibidores de la Angiogénesis/efectos adversos , Biomarcadores de Tumor/deficiencia , Progresión de la Enfermedad , Femenino , Francia , Fumarato Hidratasa/deficiencia , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Fenotipo , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , España , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Nonsense mutation or inactivation of SMARCA4 (BRG1) is associated with a monomorphic undifferentiated histological appearance in tumors at different sites. The association between SMARCA4 alteration and undifferentiated colonic carcinoma needs to be further elucidated. METHODS: A 61-year-old male patient presented to the hospital with intermittent epigastric pain in the right upper abdomen and abdominal distension. The enhanced computed tomography detected a mass in the hepatic flexure of the colon and multiple liver metastases. RESULTS: The right hemicolectomy contained a 4.5-cm undifferentiated malignancy with cells arranged in sheets, abundant necrosis, and areas showing rhabdoid morphology. The immunohistochemistry result showed that these tumor cells were focally positive for cytokeratin (CK), CK8, and CK18; however, diffusely positive for vimentin, P53, Fli-1, and SALL-4. Notably, tumor cells showed a heterogeneous loss of SMARCA4 expression pattern and intact SMARCB1 expression. Next-generation sequencing showed a germline SMARCA4 c.3277C>T(p.R1093*)mutation, somatic APC mutation, and no abnormal SMARCB1 gene. The tumor exhibited microsatellite stability, negative PD-L1 expression, and few infiltrating CD8 + T cells. The patient died a month later after surgery. CONCLUSIONS: We presented a rare case of undifferentiated colonic neoplasm with loss of SMARCA4 protein expression and germline SMARCA4 mutation. Moreover, the role of SMARCA4 alterations in tumor diagnosis and treatment was also summarized.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Neoplasias del Colon/química , Neoplasias del Colon/genética , ADN Helicasas/deficiencia , ADN Helicasas/genética , Mutación de Línea Germinal , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Resultado Fatal , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Fenotipo , Resultado del TratamientoRESUMEN
MYC rearrangements (MYC-R) confer unfavorable prognosis to large B-cell lymphomas (LBCL). Because of the low incidence of such genetic alteration, surrogates to screen MYC-R may be useful in daily practice. Previous studies suggested that clone 1A9-1 of LMO2 loss may be a good predictor for the presence of MYC-R in LBCL. The present study examines the utility of LMO2 clone SP51. For this purpose, we have analyzed 20 Burkitt lymphomas and 325 LBCL. Among them, 245 cases were studied prospectively using whole tissue sections, and 100 retrospectively by tissue microarrays. The cohort of CD10-positive prospective cases achieved the best results. Lack of LMO2 SP51 expression predicted the presence of MYC-R with high specificity, accuracy, positive and negative predictive value (PPV/NPV), and positive and negative likelihood ratios (PLR/NLR). Compared with MYC protein expression, LMO2 SP51 obtained significantly higher specificity, accuracy, PPV, and PLR (94%, 91%, 85%, and 14.33 vs 73%, 77%, 56%, and 3.26, respectively), and similar NPV and NLR (92% and 0.22 vs 95% and 0.12). Compared with LMO2 clone 1A9-1, the sensitivity of LMO2 SP51 was lower (79% vs 89%). We conclude that LMO2 SP51 may be a useful marker to screen MYC-R in CD10-positive LBCL.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Biomarcadores de Tumor , Reordenamiento Génico , Inmunohistoquímica , Proteínas con Dominio LIM/deficiencia , Linfoma de Células B Grandes Difuso/química , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas/deficiencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/deficiencia , Niño , Preescolar , Femenino , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Neprilisina/análisis , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/cirugía , Endometrio/patología , Endometrio/cirugía , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Inmunohistoquímica , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/análisis , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/deficiencia , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Supervivencia sin Progresión , Estudios Retrospectivos , Salpingooforectomía , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
FIGO grade 3 endometrioid endometrial carcinoma (EEC) is a heterogenous group of tumors with variable molecular and clinicopathologic characteristics but is treated clinically as a single entity. There is a need for additional objective markers to help guide management. The aim of this study was to evaluate a cohort of FIGO grade 3 EEC to validate the prognostic impact of molecular classification using POLE mutation (POLE-mut) analysis and immunohistochemistry for p53 and mismatch repair proteins. A secondary aim was to assess for any morphologic or immunophenotypic correlates among the molecular groups. Ninety-five cases of FIGO grade 3 EEC who underwent a hysterectomy at our institution were identified. Ten tumors (11%) harbored POLE-mut, 35 tumors (37%) showed mismatch repair deficiency, 18 tumors (19%) showed aberrant p53 staining (p53-ab), and 26 cases (27%) lacked all of these findings and were classified as no specific molecular profile. Six separate cases harbored >1 abnormality (multiple classifier), 5 of which had POLE-mut. The POLE-mut group and multiple classifier group showed excellent clinical outcomes, the p53-ab group showed the worst clinical outcomes and the 2 remaining groups showed intermediate prognosis. While the POLE-mut tumors showed a statistically significant enrichment for morphologic features including serous-like atypia and lymphocytic infiltrates, these findings were seen across all 4 molecular groups. There was no correlation between molecular grouping and tumor immunophenotypic findings, but overall 18% and 24% of tumors were completely negative for PAX-8 and estrogen receptor, respectively. Five CTNNB1 mutations were identified, 3 of which occurred in the context of a POLE-mut (including 1 multiple classifier case with MLH1/PMS2 loss). Thus our study corroborates the prognostic impact of molecular classification of high-grade endometrioid carcinoma of the uterus, achieved by readily available immunohistochemical stains in addition to POLE-mut analysis.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Carcinoma Endometrioide/genética , Análisis Mutacional de ADN , Neoplasias Endometriales/genética , Inmunohistoquímica , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/clasificación , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/patología , Reparación de la Incompatibilidad de ADN , ADN Polimerasa II/genética , Enzimas Reparadoras del ADN/deficiencia , Neoplasias Endometriales/clasificación , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Factor de Transcripción PAX8/análisis , Proteínas de Unión a Poli-ADP-Ribosa/genética , Valor Predictivo de las Pruebas , Proteína p53 Supresora de Tumor/genética , beta Catenina/genéticaRESUMEN
Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Carcinoma/enzimología , ADN Helicasas/deficiencia , Neoplasias Esofágicas/enzimología , Unión Esofagogástrica/enzimología , Proteínas Nucleares/deficiencia , Neoplasias Gástricas/enzimología , Factores de Transcripción/deficiencia , Anciano , Anciano de 80 o más Años , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/cirugía , Diferenciación Celular , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/patología , Unión Esofagogástrica/cirugía , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Nueva Gales del Sur , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Factores de Tiempo , Estados UnidosRESUMEN
OBJECTIVE: This study aimed to identify critical genes involved in the tumor biology of lung cancer via datamining of The Cancer Genome Atlas (TCGA) with special focus on gene copy number variation. METHODS: Genomic deletion and amplification were analyzed with cBioportal online tools. Relative expression of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) was analyzed by both real-time polymerase chain reaction (PCR) and Western blot. The abundance of methylthioadenosine phosphorylase (MTAP) and epithelial-mesenchymal transition markers were analyzed by real-time PCR. Cell proliferation was determined by cell counting kit-8 method and cell viability was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell migration and invasion were measured with transwell chamber assay, and migrative capacity was further evaluated by wound healing assay. RESULTS: We found the frequent loss of CDKN2A was associated with its downregulation in lung cancer, and siRNA-mediated CDNKN2A knockdown significantly stimulated cell proliferation, invasion, and migration. Mechanistically, we unraveled that MTAP, which was positively correlated with CDKN2A, predominantly mediated the antitumoral function of CDKN2A in lung cancer. CONCLUSION: Our study consolidated the involvement of CDKN2A-MTAP signaling in the context of lung cancer.