Genomic Instability in Cancer: Molecular Mechanisms and Therapeutic Potentials

Abstract

: DNA damage usually happens in all cell types, which may originate from endogenous sources, (i.e., DNA replication errors) or be emanated from radiations or chemicals. These damages range from changes in few nucleotides to large structural abnormalities on chromosomes and, if not repaired, could disturb the cellular homeostasis or cause cell death. DNA repair, as the most significant response to DNA damage, provides biological pathways by which DNA damages are corrected and returned into their natural circumstance. However, aberration in the DNA repair mechanisms may result in genomic and chromosomal instability and the accumulation of mutations. The activation of oncogenes and/or inactivation of tumor suppressor genes are serious consequence of genomic and chromosomal instability and may bring the cells into a cancerous phenotype. Therefore, genomic and chromosomal instability is usually considered as a crucial factor in the carcinogenesis and an important hallmark of various human malignancies. In the present study, we review our current understanding of the most updated mechanisms underlying genomic instability in cancer and discuss about the potential promises of these mechanisms in finding new targets for the treatment of cancer.

Apurinic/apyrimidinic nuclease 1 drives genomic evolution contributing to chemoresistance and tumorigenesis in solid tumor

“…These observations suggest that drivers of genomic instability could serve as promising targets to treat and/or prevent cancer. Consistently, it is now becoming more evident that genomic instability is a promising target in cancer 34,35 . The purpose of this study was to identify genes driving genomic instability in EAC as well as other solid tumors.…”

“…Similarly, it has been demonstrated that a genomic instability-related score calculated based on copy number alterations can predict prognosis in luminal A breast cancer 33 . It is now becoming quite evident that genomic instability is a promising target in cancer 34,35 . Chromosomal instability has been implicated in cancer progression and development of resistance to treatment and seems to associate with poor clinical outcome 13 .…”

Tumor mutation burden-related long non-coding RNAs is predictor for prognosis and immune response in pancreatic cancer

“…Nowadays, numerous studies have illuminated that cancer patients with high TMB could benefit from immunotherapy [ 12 , 39 ]. Besides, MSI and FGA are hallmarks of genomic instability which has been recognized as one of the drivers of carcinogenesis [ 40 , 41 ]. Many researchers have demonstrated that high genomic instability could be the basis for a tumor’s sensitivity to DNA-damaging therapies [ 42 ].…”

Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review)

“…The term includes changes at numerous levels, from single nucleotides to chromosomes ( 1 ), mainly in the form of microsatellite instability and chromosomal instability (CIN) ( 2 ). Genomic instability, one of the most prevalent features of human cancers, can cause cells to exhibit the cancer phenotype through mutations in oncogenes and cancer suppressor genes ( 3 ). Persistent genomic instability allows cancer cells to survive under selective pressure and adapt to their microenvironment by evolving to resist different therapies ( 4 ), and affects patient prognoses ( 5 ).…”

“…Several molecular mechanisms work together to maintain genomic stability under normal physiological conditions. For example, the precise segregation of chromosomes during mitosis and the protection of chromosome ends by telomeres ensures chromosomal stability ( 8 , 9 ), whereas DNA repair, the most important process in the DNA damage response, prevents genomic instability by efficiently repairing DNA damage ( 3 , 10 ). Dysregulation of these processes may lead to genomic instability and the development of cancer.…”