The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)related hepatocellular carcinomas (HCCs). Methods Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. Results Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. Conclusion DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes.
BackgroundMeningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies.Materials and MethodsThis retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS).ResultsForty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P < 0.001, < 0.001, 0.002, < 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014).ConclusionsNLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.
Background In recent years, non-alcoholic steatohepatitis (NASH) has become the main cause of hepatocellular carcinoma (HCC). As a means of improving the treatment of NASH-related HCCs based on early detection, this study investigated the feasibility of carcinogenic risk estimation in patients with NASH. Results Normal liver tissue (NLT), non-cancerous liver tissue showing histological findings compatible with non-alcoholic fatty liver from patients without HCC (NAFL-O), non-cancerous liver tissue showing NASH from patients without HCC (NASH-O), non-cancerous liver tissue showing non-alcoholic fatty liver from patients with HCC (NAFL-W), non-cancerous liver tissue showing NASH from patients with HCC (NASH-W) and NASH-related HCC were analyzed. An initial cohort of 171 tissue samples and a validation cohort of 55 tissue samples were used. Genome-wide DNA methylation screening using the Infinium HumanMethylation450 BeadChip and DNA methylation quantification using high-performance liquid chromatography (HPLC) with a newly developed anion-exchange column were performed. Based on the Infinium assay, 4050 CpG sites showed alterations of DNA methylation in NASH-W samples relative to NLT samples. Such alterations at the precancerous NASH stage were inherited by or strengthened in HCC samples. Receiver operating characteristic curve analysis identified 415 CpG sites discriminating NASH-W from NLT samples with area under the curve values of more than 0.95. Among them, we focused on 21 CpG sites showing more than 85% specificity, even for discrimination of NASH-W from NASH-O samples. The DNA methylation status of these 21 CpG sites was able to predict the coincidence of HCC independently from histopathological findings such as ballooning and fibrosis stage. The methylation status of 5 candidate marker CpG sites was assessed using a HPLC-based system, and for 3 of them sufficient sensitivity and specificity were successfully validated in the validation cohort. By combining these 3 CpG sites including the ZC3H3 gene, NAFL-W and NASH-W samples from which HCCs had already arisen were confirmed to show carcinogenic risk with 95% sensitivity in the validation cohort. Conclusions After a further prospective validation study using a larger cohort, carcinogenic risk estimation in liver biopsy specimens of patients with NASH may become clinically applicable using this HPLC-based system for quantification of DNA methylation.
Purpose This study was performed to identify the DNA methylation profiles underlying the clinicopathological diversity of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). Methods Genome-wide DNA methylation analysis of 88 liver tissue samples was performed using the Infinium assay. Results Principal component analysis revealed that distinct DNA methylation profiles differing from such profiles in normal control liver tissue had already been established in non-cancerous liver tissue showing NASH, which is considered to be a precancerous condition. Hierarchical clustering separated 26 NASH-related HCCs into Cluster I (n = 8) and Cluster II (n = 18). Such epigenetic clustering was significantly correlated with histopathological diversity, i.e. poorer tumor differentiation, tumor steatosis and development of a scirrhous HCC component. Significant differences in DNA methylation levels between the two clusters were accumulated in molecular pathways participating in cell adhesion and cytoskeletal remodeling, as well as cell proliferation and apoptosis. Among tumor-related genes characterizing Clusters I and II, differences in the levels of DNA methylation and mRNA expression for the SPHK1, INHBA, LTB and PDE3B genes were correlated with poorer tumor differentiation. 5-Aza-2′-deoxycytidine treatment of HCC cells revealed epigenetic regulation of the SPHK1 and LTB genes. Knockdown experiments showed that SPHK1 promotes cell proliferation, represses apoptosis and enhances migration, whereas LTB enhances migration of HCC cells. DNA hypomethylation resulting in increased expression of SPHK1 and LTB in poorly differentiated HCCs may underlie the aggressive phenotype of such HCCs. Conclusion These data indicate that DNA methylation profiles may determine the clinicopathological heterogeneity of NASH-related HCCs via alterations of tumor-related gene expression.
Skull base meningiomas (SBMs) are considered to be less aggressive and have a slower growth rate than non-SBMs. However, SBMs often develop local recurrences after surgical resection. Gross total removal is difficult because SBMs are deep-seated tumors and involve critical neurovascular structures. The treatment strategy for recurrent SBMs remains controversial. The present study aimed to evaluate the long-term clinical course and prognostic factors associated with shorter progression-free survival (PFS) of recurrent SBMs. This retrospective study included 85 recurrent SBMs from 65 patients who underwent surgery from January 2005 to September 2018. Overall survival (OS) and PFS were evaluated, and the associations among shorter PFS and age, sex, tumor size, lesions, World Health Organization (WHO) grading, removal rate, and time since prior surgery were analyzed. The median follow-up period for PFS was 68 months. The 2-, 5-, and 10-year PFS rates were 68.0%, 52.8%, and 22.7%, respectively. WHO grade II or III, multiple lesions, and tumor size were significantly associated with shorter PFS (p < 0.0001, p = 0.030, and p = 0.173, respectively). Although, radiotherapy did not improve PFS and OS for overall patients, PFS of the patients with subtotal and partial removal for WHO grade II SBMs was significantly improved by the radiotherapy. Multivariate analysis identified WHO grade II or III and multiple lesions as independent prognostic factors for shorter PFS (p < 0.0001 and p = 0.040, respectively). It is essential to estimate the risks associated with shorter PFS for patients with recurrent SBMs to aid in the development of appropriate postoperative strategies.
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