Role of genomic instability in human carcinogenesis

Abstract

This review provides various genetic and cell line data previously published in a way to explain how cellular stress can lead into genetic instability.

Keywords: Gene mutations; MYC; cellular stress; oncogene; p53; tumor suppressor gene.

Figure 1.

Accumulated mutations can promote tumor metastasis. Metastatic spread may occur throughout tumor progression, both early in tumor evolution and as the tumor evolves more genetic alterations. The metastases may then evolve to develop metastasis-specific mutations that are different to those found in the primary tumor (modified from Loeb¹²).

Figure 2.

Tumor suppressor gene classes. Three well-defined tumor suppressor classes can be defined based on the primary function of the proteins they encode. Anti-oncogenes function by encoding proteins that antagonize oncogene activity, such as with CDK4 (CDK4) and cyclin D1 (CCND1) being inhibited by the protein products of cyclin-dependent kinase inhibitor 2A (CDKN2A) and retinoblastoma (RB1). DNA damage checkpoint genes respond to DNA damage and replication stress by inducing cell death or senescence via ataxia telangiectasia mutated (ATM) and TP53. Caretaker genes such as MLH1 and BRCA1 promote genomic stability.

Figure 3.

Proposed DNA replication stress and their corresponding pathways. (a) Two proposed DNA replication stress models induced by oncogenes. Oncogenes of Model I induce double-strand breaks (DSBs) and replication stress leading to the activation of ataxia telangiectasia mutated (ATM). ATM follows by activating p53, while also disrupting the interaction of p53 with MDM2 inhibiting MDM2-dependent p53 breakdown. Model II proposes that p14ARF is activated by oncogene activity, causing MDM2 inhibition and p53 activation. It is interesting to note that loss of ATM signal can stablize ARF signal, and therefore ARF can play as a second line of defence mechasnims. (b) An alternative involving CDKN2A is believed to cause activation of p16INK4A, an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6. When CDK4 and CDK6 are combined in a complex with Cyclin D1, they act in concert to inhibit the effects of retinoblastoma 1 (RB1).

Figure 4.

Accumulated mutators can lead into full blown cancer development. While various barriers to tumor progression exist, including DNA repair processes, accumulated mutators can promote the availability of securing nutrition, fulfilling the requirement of angiogenesis and thus allow the tumor to increase in size and responses to hypoxia. Circles represent mutations in genes that result in enhanced mutagenesis, triangles indicate driver mutations that are selected on the basis of changes in the tumor microenvironment and white rectangles represent passenger mutations (Modified from Loeb¹²).