Background: Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes. Results: To better characterize the methylation changes during the malignant transformation of epithelial dysplasia, a whole-genome bisulfite sequencing analysis was performed on a series of tumor, dysplastic, and non-neoplastic epithelial tissue samples from esophageal squamous cell carcinoma (ESCC) patients. Promoter hypermethylation in TGF-β receptor type II (TGFBR2), an important mediator of TGF-β signaling, was identified. Further, we evaluated the methylation and expression of TGFBR2 in tumor samples through The Cancer Genome Atlas multiplatform data as well as immunohistochemistry. Moreover, treatment of ESCC cell lines with5-Aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, reactivated the expression of TGFBR2. The lentiviral mediating the overexpression of TGFBR2 inhibited the proliferation of ESCC cell line by inducing cell cycle G2/M arrest. Furthermore, the overexpression of TGFBR2 inhibited the tumor growth obviously in vivo. Conclusions: The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.
Purpose Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs. Methods Next-generation sequencing was carried out on mucosal melanoma samples ( n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction. Results In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs ( n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT ( P < 0.05). Kaplan–Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis. Conclusion These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.
Recurrence is the major reason for mortality after hepatectomy or liver transplantation surgery for hepatocellular carcinoma (HCC). [1][2][3][4] It is difficult to precisely manage adjuvant therapy to prevent recurrence after surgery. Here, we demonstrated that an integrated strategy of monitoring circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) could accurately detect minimal residual disease (MRD) and precisely predict recurrence in patients with HCC. [5][6][7] A total of 80 patients with HCC were enrolled in this study, and 66 were eligible for analysis using postoperative serial blood samples (Figure 1A, Figure S1; Table S1). CTCs were positively selected by the asialoglycoprotein receptor using a microfluidic system and identified with pancytokeratins (Figure 1B). The first postoperative blood samples were analyzed for recurrence risk evaluation. Postoperative CTC positivity was significantly correlated with worse recurrence-free survival (RFS) rates, with a sensitivity of 75% and specificity of 86.8% (p < .0001; hazard ratio [HR] 8.40, 95% confidence interval [CI] = 3.52-20.05) (Figure 2A, Table S2). To assess the ctDNA fraction, we first tested an approach using a personalized panel targeting mutations from whole-exome sequencing (PPWES). Briefly, we performed WES on the tumour samples and selected ∼15 somatic mutations for each case (Tables S4, S5). A personalized assay was designed to profile the mutations in the matched ctDNA sample with mutation-capsule technology (MCT). 8,9 ctDNA PPWES positivity, defined as one or more mutations detected in cfDNA, was strongly associated with a worse RFS rate (p < .0001; HR 11.77, 95% CI = 4.96-27.96), with 70.4% sensitivity and 93.8% specificity (Figure 2B, Table S2). The association between postoperative alpha-fetoprotein (AFP) and des-gammacarboxy prothrombin (DCP) positivity and poor RFS rates was significant
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