Геномная нестабильность и мутации

Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011

Acquisition of the multiple hallmarks enumerated above depends in large part on a succession of alterations in the genomes of neoplastic cells. Simply depicted, certain mutant genotypes confer selective advantage on subclones of cells, enabling their outgrowth and eventual dominance in a local tissue environment. Accordingly, multistep tumor progression can be portrayed as a succession of clonal expansions, each of which is triggered by the chance acquisition of an enabling mutant genotype. Because heritable phenotypes, e.g., inactivation of tumor suppressor genes, can also be acquired through epigenetic mechanisms such as DNA methylation and histone modifications, some clonal expansions may well be triggered by nonmutational changes affecting the regulation of gene expression.

The extraordinary ability of genome maintenance systems to detect and resolve defects in the DNA ensures that rates of spontaneous mutation are usually very low during each cell generation. In the course of acquiring the roster of mutant genes needed to orchestrate tumorigenesis, cancer cells often increase the rates of mutation. This mutability is achieved through increased sensitivity to mutagenic agents, through a breakdown in one or several components of the genomic maintenance machinery, or both. In addition, the accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis. The role of TP53 is central here, leading to its being called the «guardian of the genome».

A diverse array of defects affecting various components of the DNA-maintenance machinery—often referred to as the “caretakers” of the genome — have been documented. The catalog of defects in these caretaker genes includes those whose products are involved in (1) detecting DNA damage and activating the repair machinery, (2) directly repairing damaged DNA, and (3) inactivating or intercepting mutagenic molecules before they have damaged the DNA. From a genetic perspective, these caretaker genes behave much like tumor suppressor genes, in that their functions can be lost during the course of tumor progression, with such losses being achieved either through inactivating mutations or via epigenetic repression. Mutant copies of many of these caretaker genes have been introduced into the mouse germline and result, predictably, in increased cancer incidence, supporting their potential involvement in human cancer development.

In the decade since we first enumerated the cancer hallmarks, another major source of tumor-associated genomic instability has been uncovered: as described earlier, the loss of telomeric DNA in many tumors generates karyotypic instability and associated amplification and deletion of chromosomal segments. When viewed in this light, telomerase is more than an enabler of the hallmark capability for unlimited replicative potential and must also be added to the list of critical caretakers responsible for maintaining genome integrity.

Advances in the molecular-genetic analysis of cancer cell genomes have provided the most compelling demonstrations of function-altering mutations and of ongoing genomic instability during tumor progression. One type of analysis—comparative genomic hybridization (CGH)—documents the gains and losses of gene copy number across the cell genome; in many tumors, the pervasive genomic aberrations revealed by CGH provide clear evidence for loss of control of genome integrity. Importantly, the recurrence of specific aberrations (both amplifications and deletions) at particular sites in the genome indicates that such sites are likely to harbor genes whose alteration favors neoplastic progression.

More recently, with the advent of efficient and economical DNA-sequencing technologies, higher-resolution analyses have become possible. Early studies are revealing distinctive patterns of DNA mutations in different tumor types (see http://cancergenome.nih.gov/). In the not-too-distant future, the sequencing of entire cancer cell genomes promises to clarify the prevalence of ostensibly random mutations scattered across cancer cell genomes. Thus, recurring genetic alterations may point to a causal role of particular mutations in tumor pathogenesis.

Although the specifics of genome alteration vary dramatically between different tumor types, the large number of genome maintenance and repair defects that have already been documented in human tumors, together with abundant evidence of widespread destabilization of gene copy number and nucleotide sequence, persuade us that instability of the genome is inherent to the great majority of human cancer cells. This leads, in turn, to the conclusion that the defects in genome maintenance and repair are selectively advantageous and therefore instrumental for tumor progression, if only because they accelerate the rate at which evolving premalignant cells can accumulate favorable genotypes. As such, genome instability is clearly an enabling characteristic that is causally associated with the acquisition of hallmark capabilities.


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