RESUMEN
The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Asunto(s)
Carcinoma Endometrioide , Metilación de ADN , Hiperplasia Endometrial , Neoplasias Endometriales , Epigénesis Genética , Fosfohidrolasa PTEN , Femenino , Humanos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Fosfohidrolasa PTEN/genética , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Mutación , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Islas de CpG/genética , AncianoRESUMEN
AIM: To investigate mortality reduction from gastric cancer based on the results of endoscopic screening. METHODS: The study population consisted of participants of gastric cancer screening by endoscopy, regular radiography, and photofluorography at Niigata city in 2005. The observed numbers of cumulative deaths from gastric cancers and other cancers were accumulated by linkage with the Niigata Prefectural Cancer Registry. The standardized mortality ratio (SMR) of gastric cancer and other cancer deaths in each screening group was calculated by applying the mortality rate of the reference population. RESULTS: Based on the results calculated from the mortality rate of the population of Niigata city, the SMRs of gastric cancer death were 0.43 (95%CI: 0.30-0.57) for the endoscopic screening group, 0.68 (95%CI: 0.55-0.79) for the regular radiographic screening group, and 0.85 (95%CI: 0.71-0.94) for the photofluorography screening group. The mortality reduction from gastric cancer was higher in the endoscopic screening group than in the regular radiographic screening group despite the nearly equal mortality rates of all cancers except gastric cancer. CONCLUSION: The 57% mortality reduction from gastric cancer might indicate the effectiveness of endoscopic screening for gastric cancer. Further studies and prudent interpretation of results are needed.
Asunto(s)
Detección Precoz del Cáncer/métodos , Gastroscopía , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Adulto , Anciano , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Radiografía , Sistema de Registros , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/prevención & control , Factores de TiempoRESUMEN
AIM: To discuss the efficacy of endoscopic mass screening for gastric cancer. METHODS: The data used in this study were the results of mass screening programs for gastric cancer in Niigata City from 2002 to 2004. The number of participants was 35,089 in 2002, 34,557 in 2003 and 36,600 in 2004. The finding ratio referred to the final diagnosis of gastric cancer after a double check of endoscopic files and histological findings. The costs of identifying one case of gastric cancer were calculated based on the total expense for each screening program and additional close examinations. RESULTS: From the analysis of individual screening program with endoscopy, individual screening program with X-ray (ISX) and mass screening program with photofluorography (MSP) in reference to the finding ratio of gastric cancer, endoscopic examination was the best for detecting early gastric cancer, the finding ratio was 0.87% in 2004, approximately 2.7 and 4.6 times higher than those of the ISX and MSP groups. In addition, this novel method was the cheapest means regarding the cost of identifying one case of gastric cancer, which was estimated to be 1,608,000 Japanese yen in 2004. CONCLUSION: Endoscopic mass screening is a promising method and can be effectively applied if a sufficient number of skilled endoscopists become available to staff the system and if city offices support it.
