RESUMEN
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Neoplasias del Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas Tirosina Quinasas Receptoras/genética , Adenoma/genética , Adenoma/patología , Animales , Neoplasias del Colon/genética , Humanos , Hiperplasia/genética , Hiperplasia/patología , Ratones , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a distinct variant of HCC that is characterized by dense tumor-infiltrating lymphocytes (TILs). Patients with LEL-HCC also show better clinical outcomes compared to conventional HCC (c-HCC), which is commonly presented with low TIL. Emerging evidence has begun to highlight tumor-intrinsic genetic abnormalities in the tumor-host immune interfaces. However, genome-wide characterization of LEL-HCC remains largely unexplored. Here, we defined the genomic landscape of 12 LEL-HCC using whole-exome sequencing, and further underpinned those genetic alterations related to an immune active microenvironment by comparing findings to 15 c-HCC that were sequenced in parallel. Overall, the mutational load between LEL-HCC and c-HCC was similar. Interestingly, SNV incidences of specific genes (CTNNB1, AXIN1, NOTCH1, and NOTCH2) were significantly higher in c-HCC than LEL-HCC, suggesting a plausible link between activated Wnt/ß-catenin and Notch signaling pathways and immune avoidance. Marked focal amplification of chromosome 11q13.3 was prevalent in LEL-HCC. Using The Cancer Genome Atlas dataset, we further established oncogenes expressed from chromosome 11q13.3 (CCND1, FGF19, and FGF4) to be strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Our results have illustrated for the first time the somatic landscape of LEL-HCC, and highlighted molecular alterations that could be exploited in combinatory therapy with checkpoint inhibitors in targeting HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Linfocitos Infiltrantes de Tumor/patología , Anciano , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Variaciones en el Número de Copia de ADN , Femenino , Amplificación de Genes , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Transducción de Señal , Microambiente Tumoral , Secuenciación del ExomaRESUMEN
INTRODUCTION: Patients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized cancer treatment decisions. PATIENTS AND METHODS: A consecutive cohort of 789 resected NSCLC cases were reviewed. Fifty-nine NSCLC cases lacking morphologic differentiation, accounting for 7.5% of all resected NSCLCs, were identified and further characterized by immunohistochemistry according to the 2015 WHO lung tumor classification. Molecular alterations were investigated by multiple technologies including target capture sequencing, immunohistochemistry, and fluorescence in situ hybridizations. RESULTS: Of 59 NSCLC cases lacking morphologic differentiation, 20 (33.9%) were reclassified as adenocarcinoma (LCC-AD), 14 (23.7%) as squamous cell carcinoma (LCC-SqCC), and 25 (42.4%) as LCC-Null. Approximately 92% of LCC-Null, 95% of LCC-AD, and 86% of LCC-SqCC harbored clinically relevant alterations. Alterations characteristic of adenocarcinoma (EGFR, KRAS, ALK receptor tyrosine kinase [ALK], ROS1, and serine/threonine kinase 11 [STK11]) were detected in the LCC-AD subgroup but not in LCC-SqCC, whereas squamous-lineage alterations (phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha [PIK3CA], SRY-box 2 [SOX2], fibroblast growth factor receptor 1 [FGFR1], and AKT1) were detected in the LCC-SqCC subgroup but not in the LCC-AD group. Although some LCC-Null tumors displayed a genetic profile similar to either adenocarcinoma or squamous-cell carcinoma, more than half of the LCC-Null group were completely devoid of recognizable lineage-specific genetic profiles. High programmed death ligand 1 expression and high frequency of cell cycle regulatory gene alterations were found in the LCC-Null group offering alternative options of targeted therapy. CONCLUSIONS: This comprehensive molecular study provided further insight into the genetic architecture of LCC. The presence of clinically actionable alterations in a majority of the tumors allowed personalized treatment to emerge.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Grandes/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutación , Adenocarcinoma del Pulmón/clasificación , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma de Células Grandes/clasificación , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/clasificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/clasificación , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , MicroARNs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , ARN Viral/genética , Regiones no Traducidas 3' , Animales , Proteínas de la Ataxia Telangiectasia Mutada/biosíntesis , Sitios de Unión , Línea Celular Tumoral , Daño del ADN , Represión Enzimática , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Interacciones Huésped-Patógeno , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Carcinoma Nasofaríngeo/enzimología , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/virología , Transcriptoma , Latencia del VirusRESUMEN
AIMS: Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well-differentiated HCC. However, the clinicopathological features and pathogenesis of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC. METHODS AND RESULTS: A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow-up was 45.5 (range: 0.2-166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein-1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin-like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks [diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%)], underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha-fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non-anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism. CONCLUSION: Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse.
Asunto(s)
Carcinoma Hepatocelular/patología , Hígado Graso/patología , Neoplasias Hepáticas/patología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/mortalidad , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hiperlipidemias/epidemiología , Hipertensión/epidemiología , Inmunohistoquímica , Estimación de Kaplan-Meier , Lipasa/genética , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/mortalidad , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Análisis de Matrices TisularesRESUMEN
PURPOSE: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non-small cell lung carcinoma (NSCLC). EXPERIMENTAL DESIGN: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively. RESULTS: METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis. CONCLUSIONS: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048-56. ©2016 AACRSee related commentary by Drilon, p. 2832.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Variaciones en el Número de Copia de ADN/genética , Dosificación de Gen/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-met/genética , Sitios de Empalme de ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación/genética , Pronóstico , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014-2015, an emergent variant of a previously rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root-to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross-protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored.