Cells are exposed to multiple endogenous and exogenous stresses daily, some of which can induce DNA damage, a major source of genomic instability. To deal with damaged DNA and maintain genomic integrity, cells have evolved complicated DNA damage repair (DDR) machinery. Impaired DDR pathways can lead to the accumulation of DNA damage and genomic instability, a risk factor for carcinogenesis. If cancer occurs, DDR is normally associated with increased survival of tumor cells and the development of treatment resistance. Increasingly, evidence shows that the activity of DDR pathways not only impact the outcomes of cytotoxic treatments, but also multiple aspects of anti-tumor immunity. As such, DDR deficiency is emerging as a promising prognostic factor in predicting the therapeutic outcomes of immunotherapy. Accordingly, modulation of DDR pathways can improve immunotherapeutic efficiency in cancer treatment. In this review, we outline the mechanisms of DNA damage, the DDR pathways which counteract them and summarize the association between altered DDR pathways and cancer. Additionally, we highlight DDR deficiency in the context of cancer immunity, and its potential applications in the combined treatment of cancer.
Leukemia is a polyclonal and progressive disease with drastic intra-clone heterogeneity. During the early stages of disease development, it is mostly shaped by the deterministic effects of key initiating events, which could establish the roles of genomic instability and cell plasticity in clonal evolution. Later, preleukemic cells acquire successive genetic mutations, undergoing distinct evolutionary trajectories. In this review, we summarize the current understanding of how genetic lesions define distinct clonal architectures. We further highlight two classical evolutionary models and their relevant prognostic implications. Given that drug selection pressure remains a major driving force of relapse, we also discuss recurrent patterns of clonal evolution under chemotherapy and targeted therapy. Understanding the rationale for directing distinct clonal evolution patterns will be instrumental in the development of different therapeutic strategies to prevent or overcome drug resistance and relapse during disease progression.
Hepatocellular carcinoma (HCC) is a subtype of highly malignant carcinoma that occurs in the liver, improved understanding of the mechanisms behind HCC tumorigenesis and better clinical treatment options are urgently needed. Several pieces of evidence have implied that the tumorigenesis and progression of HCC are driven by various genomic mutations and alterations. In this review, we have provided an overview of driver mutations in different signaling pathways that dominate HCC tumorigenesis, as well as vital molecular events in HCC initiation. Meanwhile, we have also summarized different agents or tools that may be utilized for HCC treatment in patients with corresponding mutation events. These findings may expand our understanding of the inherent characteristics of HCC and provide new perspectives for the future clinical treatment of HCC.