Role of genomic instability in human carcinogenesis

Abstract

Genomic instability has been an area of active area of research in the last two decades. Based on the initial study for hereditary cancers, DNA repair gene family mutations have been identified. In sporadic (non-hereditary) cancers, several large-scale DNA sequencing studies suggest that mutations in DNA repair genes are less frequent, suggesting the complexity of tumorigenesis of sporadic cancers. So far, several important genes have been identified, by using mostly cell line models and mice studies. These include DNA damage response modifier like ataxia telangiectasia mutated (ATM), conventional tumor suppressor genes like TP53 and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF). Various hypotheses for sporadic tumorigenesis have been developed, and so far, "oncogene-induced DNA replication stress model" has been gaining widespread interests. In this review, we will first describe some of the important concepts of genomic instability. Then, we will outline oncogene-induced genomic instability and discuss the role of the MYC gene during this process, which will be followed by detailed reviews of mutation data. We hope that this review can outline the overall perspectives of genomic instability.

CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

“…However, genomic DNA molecules are highly susceptible to damage from a variety of factors [ 1 ]. Once DNA is damaged by external radiation, chemotherapeutic drugs, or intrinsic factors, efficient and accurate DNA damage responses will be initiated to repair damaged DNA to ensure genomic integrity [ 2 ], thereby preventing malignant transformation [ 3 ].…”

<p>LINC00958-MYC positive feedback loop modulates resistance of head and neck squamous cell carcinoma cells to chemo- and radiotherapy in vitro</p>

“…HNSCC risk factors include tobacco smoking, alcohol consumption, infection of Epstein-Barr virus (EBV), human papilloma virus (HPV), or consumption of salted fish and meats 3–5. These risk factors induce genetic instability6 and alter expression of different genes to activate oncogenes, but inactivate tumor suppressor genes to transform normal HN epithelium to tumor cells 7,8. To date, concurrent chemoradiotherapy is a standard treatment option in the management of locally advanced HNSCC,9 although numbers of HNSCC patients showed eventual resistance to chemotherapy and radiotherapy, which leads to dismal treatment response and relapse and poor prognosis 10.…”

Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscape

“…Each cluster exhibits a characteristic deregulation of pathways; however, cluster 2 barely has four unique sub-pathways, all related to common hallmarks ‘Resisting cell death’ and ‘Sustaining proliferative signaling’. Neoplastic clusters 1 and 3, but not cluster 2, exhibit ‘Genome instability’, a hallmark observed in almost all sporadic human cancers, including glioblastoma ( 70 , 71 ). Besides, clusters 1 and 3 show deregulated ‘Cellular energetics’, a process that has been suggested as a suitable target for tumor cell elimination ( 72 ).…”