Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets.

Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

THSD7B Mutation Induces Platinum Resistance in Small Cell Lung Cancer Patients.

Aim: Several cases of small cell lung cancer (SCLC) patients demonstrate resistance to the treatment initiatives such as cisplatin after platinum chemotherapy. It is crucial to the improvement of the overall survival (OS) of SCLC patients to discover the gene mutation inducing platinum resistance within this cohort. Patients and Methods: We analyzed the gene mutations significantly associated with the OS from 2 cohorts of SCLC platinum-treated patients. And then we screened out THSD7B mutation. In order to understand the mechanism between THSD7B mutation and platinum resistance, we designed gene mutation co-occurrence and mutual exclusivity analysis, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) analysis, and Connectivity Map (CMap) analysis. Results: The poor prognosis of THSD7B mutant patients may be related to the inhibition of cell death-related pathways, the up-regulation of cell invasion and metastasis pathways, and the down-regulation of immune response pathways. Lovastatin and cyclooxygenase inhibitors could be used as potential target compounds in THSD7B mutant patients, which provides reference for future research on platinum resistance. Conclusion: THSD7B can be considered a reliable biomarker that effectively facilitates the prediction of poor survival in SCLC platinum-treated patients.

CAMSAP1 Mutation Correlates With Improved Prognosis in Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy.

Platinum-based chemotherapy is the first-line treatment for small cell lung cancer (SCLC). However, due to patients developing a resistance to the drug, most experience relapse and their cancer can become untreatable. A large number of recent studies have found that platinum drug sensitivity of various cancers is affected by specific gene mutations, and so with this study, we attempted to find an effective genetic biomarker in SCLC patients that indicates their sensitivity to platinum-based drugs. To do this, we first analyzed whole exome sequencing (WES) and clinical data from two cohorts to find gene mutations related to the prognosis and to the platinum drug sensitivity of SCLC patients. The cohorts used were the Zhujiang cohort (N = 138) and the cohort reported by George et al. (N = 101). We then carried out gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate possible molecular mechanisms through which these gene mutations affect patient prognosis and platinum drug sensitivity. We found that for SCLC patients, CAMSAP1 mutation can activate anti-tumor immunity, mediate tumor cell apoptosis, inhibit epithelial-mesenchymal transition (EMT), improve prognosis, and improve platinum drug sensitivity, suggesting that CAMSAP1 mutation may be a potential biomarker indicating platinum drug sensitivity and patient prognosis in SCLC.

A comparison of the efficacy of antiangiogenic agents combined with chemotherapy for the treatment of non-small cell lung cancer: a network meta-analysis.

OBJECTION: To explore the effects of combinations of antiangiogenic agents and chemotherapy agents on non-small cell lung cancer (NSCLC) patients and indirectly compare the therapeutic effect of Endostar combined with chemotherapy and bevacizumab combined with chemotherapy on NSCLC. METHODS: We searched 3 electronic databases: PubMed, Web of Science and the Cochrane Library. The ORRs, HRs and 95% confidence intervals of OS and PFS were used to compare the efficacy of Endostar combined with chemotherapy and bevacizumab combined with chemotherapy. We use the Bayesian network meta-analysis method to make indirect comparisons and obtain rank probabilities; in addition, we used single-arm meta-analysis to synthesize the existing data. RESULTS: A total of 29 studies were included in the analysis. Among them, we included a total of 14 interventions. A total of 12,862 patients participated in this analysis. The single-arm meta-analysis showed that the pooled ORR and 95% CI were 0.35 (0.31, 0.39), the pooled HR of OS and 95% CI were 0.89 (0.81, 0.98), and the pooled HR of PFS and 95% CI were 0.67 (0.56, 0.81). According to the results of network meta-analysis, there were no significant differences between the 5 kinds of bevacizumab combined with chemotherapy regimens and the 4 kinds of Endostar combined with chemotherapy regimens for improving ORR and prolonging OS and PFS. The rank probabilities suggested that in terms of ORR, Pla + Pem + Bev was the first-ranked intervention (0.288). Pla + Pem + Endo was the first-ranked intervention for prolonging OS (0.423) and Pla + Gem + Endo was the first-ranked intervention for prolonging PFS (0.302). CONCLUSION: Antiangiogenic agents combined with platinum-containing dual drugs can provide benefits to NSCLC patients. In addition, bevacizumab combined with chemotherapy regimens has better theraputic effect on ORR while Endostar combined with chemotherapy may have better effects on OS and PFS for the treatment of NSCLC patients.