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Abstract Background The treatment for colon adenocarcinoma (COAD) faces challenges in terms of immunotherapy effectiveness due to multiple factors. Because of the high tumor specificity and immunogenicity, neoantigen has been considered a pivotal target for cancer immunotherapy. Therefore, this study aims to identify and predict the potential tumor antigens of MUC somatic mutations (MUCmut) in COAD. Methods Three databases of TCGA, TIMER2.0, and cBioPortal were used for a detailed evaluation of the association between MUCmut and multi-factors like tumor mutation burden (TMB), microsatellite instability (MSI), prognosis, and the tumor microenvironment within the context of total 2242 COAD patients. Next, TSNAdb and the differential agretopicity index (DAI) were utilized to predict high-confidence neopeptides for MUCmut based on 531 COAD patients’ genomic information. DAI was calculated by subtraction of its predicted HLA binding affinity of the MUCmut peptide from the corresponding wild-type peptide. Results The top six mutation frequencies (14 to 2.9%) were from MUC16, MUC17, MUC5B, MUC2, MUC4 and MUC6. COAD patients with MUC16 and MUC4 mutations had longer DFS and PFS. However, patients with MUC13 and MUC20 mutations had shorter OS. Patients with the mutation of MUC16, MUC5B, MUC2, MUC4, and MUC6 exhibited higher TMB and MSI. Moreover, these mutations from the MUC family were associated with the infiltration of diverse lymphocyte cells and the expression of immune checkpoint genes. Through TSNAdb 1.0/NetMHCpan v2.8, 452 single nucleotide variants (SNVs) of MUCmut peptides were identified. Moreover, through TSNAdb2.0/NetMHCpan v4.0, 57 SNVs, 1 Q-frame shift (TS), and 157 short insertions/deletions (INDELs) of MUCmut were identified. Finally, 10 high-confidence neopeptides of MUCmut were predicted by DAI. Conclusions Together, our findings establish the immunogenicity and therapeutic potential of mutant MUC family-derived neoantigens. Through combining the tools of TSNAdb and DAI, a group of novel MUCmut neoantigens were identified as potential targets for immunotherapy.

BackgroundThe SCF (Skp1-cullin-F-box proteins) complex is the largest family of E3 ubiquitin ligases that mediate multiple specific substrate proteins degradation. Two ring-finger family members RBX1/ROC1 and RBX2/RNF7/SAG are small molecular proteins necessary for ubiquitin ligation activity of the multimeric SCF complex. Accumulating evidence indicated the involvement of RBX proteins in the pathogenesis and development of cancers, but no research using pan-cancer analysis for evaluating their difference has been directed previously.MethodsWe investigated RBX1/2 expression patterns and the association with clinicopathological features, and survivals of cancer patients obtained from the TCGA pan-cancer data. The binding energies of RBX1/2-CUL1 complexes were preliminarily calculated by using molecular dynamics simulations. Meanwhile, we assessed their immune infiltration level across numerous databases, including TISIDB and Timer database.ResultsHigh expression levels of RBX1/2 were observed in most cancer types and correlated with poor prognosis of patients analyzed. Nonetheless, exceptions were observed: RBX2 expression in KICH was higher than normal renal tissues and played a detrimental role in KICH. The expression of RBX1 was not associated with the prognostic risk of KICH. Moreover, the combination of RBX1 and CUL1 expression is more stable than that of RBX2 and CUL1. RBX1/2 expression showed their own specific characteristics in tumor pathological stages and grades, copy number variation and immune components.ConclusionsThese findings not only indicated that the difference of RBX1/2 might result in varying degrees of tumor progression, but also suggested that they might serve as biomarkers for immune infiltration in cancers, shedding new light on therapeutics of cancers.

Hundreds of DNA repair proteins coordinate together to remove the diverse damages for ensuring the genomic integrity and stability. The repair system is an extensive network mainly encompassing cell cycle arrest, chromatin remodeling, various repair pathways, and new DNA fragment synthesis. Acetylation on DNA repair proteins is a dynamic epigenetic modification orchestrated by lysine acetyltransferases (HATs) and lysine deacetylases (HDACs), which dramatically affects the protein functions through multiple mechanisms, such as regulation of DNA binding ability, protein activity, post-translational modification (PTM) crosstalk, and protein–protein interaction. Accumulating evidence has indicated that the aberrant acetylation of DNA repair proteins contributes to the dysfunction of DNA repair ability, the pathogenesis and progress of cancer, as well as the chemosensitivity of cancer cells. In the present scenario, targeting epigenetic therapy is being considered as a promising method at par with the conventional cancer therapeutic strategies. This present article provides an overview of the recent progress in the functions and mechanisms of acetylation on DNA repair proteins involved in five major repair pathways, which warrants the possibility of regulating acetylation on repair proteins as a therapeutic target in cancers.

Abstract Protocadherin18 (PCDH18) was found to be preferentially methylated and inactivated in colorectal cancer (CRC) using bioinformatics tools. However, its biologic role in tumorgenesis remains unclear. Herein, we aimed to elucidate its epigenetic regulation and biological functions in CRC. The methylation status of PCDH18 was significant higher in CRC tissues than in adjacent non-tumor tissues (median, 15.17% vs. median, 0.4438%). Expression level of PCDH18 was significantly lower in primary CRCs than in nonmalignant tissues. Importantly, methylation status of PCDH18 in cell-free DNA of CRC patients was also significantly higher than in healthy subjects. PCDH18 was readily expressed in NCM460 cells, but downregulated in 100% (4/4) of CRC cell lines by promoter methylation, despite its expression could be restored through demethylation treatment. Overexpression of PCDH18 suppressed CRC cell viability, colony formation and migration. Meanwhile, the depletion of PCDH18 by siRNA in NCM460 cells enhanced the colonogenicity and migration ability and promoted β-catenin nuclear accumulation, whereas it inhibited cell cycle arrest. These effects were associated with upregulation of phospho-GSK-3β and cyclin D1, and downregulation of caspase3 and p21. Our results suggested that PCDH18 was a putative tumor suppressor with epigenetic silencing in CRC and a potential biomarker for CRC diagnosis.

Background. Adenomatous polyposis coli (APC) is widely known as an antagonist of the Wnt signaling pathway via the inactivation of β-catenin. An increasing number of studies have reported that APC methylation contributes to the predisposition to breast cancer (BC). However, recent studies have yielded conflicting results. Methods. Herein, we systematically carried out a meta-analysis to assess the correlation between APC methylation and BC risk. Based on searches of the Cochrane Library, PubMed, Web of Science and Embase databases, the odds ratio (OR) with 95% confidence interval (CI) values were pooled and summarized. Results. A total of 31 articles involving 35 observational studies with 2,483 cases and 1,218 controls met the inclusion criteria. The results demonstrated that the frequency of APC methylation was significantly higher in BC cases than controls under a random effect model (OR = 8.92, 95% CI [5.12–15.52]). Subgroup analysis further confirmed the reliable results, regardless of the sample types detected, methylation detection methods applied and different regions included. Interestingly, our results also showed that the frequency of APC methylation was significantly lower in early-stage BC patients than late-stage ones (OR = 0.62, 95% CI [0.42–0.93]). Conclusion. APC methylation might play an indispensable role in the pathogenesis of BC and could be regarded as a potential biomarker for the diagnosis of BC.

OBJECTIVE: The prognostic significance of CD24 expression for survival in patients with gastric cancer remains controversial. We conducted a meta-analysis to investigate the impact of CD24 expression on clinicopathological features and survival outcomes in gastric cancer. METHODS: A comprehensive literature search of the electronic databases PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI; up to April 8, 2014) was performed for relevant studies using multiple search strategies. Correlations between CD24 expression and clinicopathological features and overall survival (OS) were analyzed. RESULTS: A total of 1,041 patients with gastric cancer from 9 studies were included. The pooled odds ratios (ORs) indicated CD24 expression was associated with tumor depth (OR = 0.45, 95% confidence interval [CI] = 0.32-0.63; P