Background: Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study, we determined the relevant players and role of N ⁶ -methyladenine (m ⁶ A) RNA methylation in cervical cancer progression. Methods: The roles of m ⁶ A RNA methylation and centromere protein K (CENPK) in cervical cancer were analyzed using bioinformatics analysis. Methylated RNA immunoprecipitation was adopted to detect m ⁶ A modification of CENPK mRNA. Human cervical cancer clinical samples, cell lines, and xenografts were used for analyzing gene expression and function. Immunofluorescence staining and the tumorsphere formation, clonogenic, MTT, and EdU assays were performed to determine cell stemness, chemoresistance, migration, invasion, and proliferation in HeLa and SiHa cells, respectively. Western blot analysis, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter, cycloheximide chase, and cell fractionation assays were performed to elucidate the underlying mechanism. Results: Bioinformatics analysis of public cancer datasets revealed firm links between m ⁶ A modification patterns and cervical cancer prognosis, especially through ZC3H13-mediated m ⁶ A modification of CENPK mRNA. CENPK expression was elevated in cervical cancer, associated with cancer recurrence, and independently predicts poor patient prognosis [hazard ratio = 1.413, 95% confidence interval = 1.078 − 1.853, P = 0.012]. Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo ( P < 0.001). We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK with β-catenin, which promoted β-catenin expression and nuclear translocation, facilitated p53 ubiquitination, and led to activation of Wnt/β-catenin signaling, but suppression of the p53 pathway. This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness, DNA damage repair pathways necessary for cisplatin/carboplatin resistance, epithelial-mesenchymal transition involved in metastasis, and DNA replication that drove tumor cell proliferation. Conclusions: CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.

Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of CCND1 amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database (n = 6,536), The Cancer Genome Atlas (TCGA) database (n = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database (n = 10,109). Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs. A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8⁺ T cells, dendritic cells (DCs), and B cells in the TME in a TCGA CCND1 amplification population. The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial–mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.

The PRKDC gene encodes the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) protein. DNA-PKcs plays an important role in nonhomologous end joining (NHEJ) of DNA double-strand breaks (DSBs) and is also closely related to the establishment of central immune tolerance and the maintenance of chromosome stability. The occurrence and development of different types of tumors and the results of their treatment are also influenced by DNA-PKcs, and it may also predict the results of radiotherapy, chemotherapy, and therapy with immune checkpoint inhibitors (ICIs). Here, we discuss and review the structure and mechanism of action of PRKDC and DNA-PKcs and their relationship with cancer.

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA‐activated, catalytic subunit ( PRKDC ) is an important gene for DNA double‐strand break (DSB) repair and central T‐cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole‐exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel‐based sequencing data of 3877 solid tumor samples from Geneplus‐Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI‐treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild‐type samples ( P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8 ⁺ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild‐type samples ( P < 0.05). In ICI‐treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255–0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715–0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155–0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058–0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co‐exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.

Background: SETD2 protects against genomic instability via maintenance of homologous recombination repair (HRR) and mismatch repair (MMR) in neoplastic cells. However, it remains unclear whether SETD2 dysfunction is a complementary or independent factor to microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) for immunocheckpoint inhibitor (ICI) treatment, and little is known regarding whether this type of dysfunction acts differently in various types of cancer. Methods: This cohort study used multidimensional genomic data of 6726 sequencing samples from our cooperative and non-public GenePlus institute from April 1 through April 10, 2020. MSIsensor score, HRD score, RNAseq, mutational data, and corresponding clinical data were obtained from the TCGA and MSKCC cohort for seven solid tumor types. Results: A total of 1021 genes underwent target panel sequencing reveal that SETD2 mutations were associated with a higher TMB. SETD2 deleterious mutation dysfunction affected ICI treatment prognosis independently of TMB-H (p < 0.01) and had a lower death hazard than TMB-H in pancancer patients (0.511 vs 0.757). Significantly higher MSI and lower homologous recombination deficiency were observed in the SETD2 deleterious mutation group. Improved survival rate was found in the MSKCC-IO cohort (P < 0.0001) and was further confirmed in our Chinese cohort. Conclusion: We found that SETD2 dysfunction affects ICI treatment prognosis independently of TMB-H and has a lower death hazard than TMB-H in pancancer patients. Therefore, SETD2 has the potential to serve as a candidate biomarker for ICI treatment. Additionally, SETD2 should be considered when dMMR is detected by immunohistochemistry.

Most patients with advanced hepatocellular carcinoma (HCC) ultimately experience tumor progression after first-line systemic therapies. Systemic therapy is generally recommended as second-line treatment for advanced HCC in the major guidelines. Combining apatinib with hepatic arterial infusion chemotherapy (HAIC) likely drives synergistic activity on advanced HCC with extrahepatic metastasis. This phase II trial (ChiCTR2000029082) aimed to assess efficacy and safety of this combination in patients with HCC with extrahepatic metastasis who have progressed after first-line systemic therapies. The primary end point was the objective response rate (ORR). The secondary endpoints were progress-free survival (PFS), disease control rate (DCR), 6- and 12-month survival rates, overall survival (OS), and adverse events (AEs). Thirty-nine patients received oral treatment with apatinib, and hepatic artery infusion oxaliplatinplus raltitrexed. Per RECIST v1.1, the ORR and DCR was 53.8% and 89.7% in the patients population, respectively. The median PFS and OS was 6.2 months and 11.3 months, respectively. The 6- and 12-month survival rates were 81.7% and 44.1%, respectively. All AEs were manageable by medication or dose modifications. Apatinib plus HAIC for second-line therapy in advanced HCC with extrahepatic metastasis shows promising efficacy and manageable toxicities.