The two sides of chromosomal instability: drivers and brakes in cancer

Abstract

Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule-kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the "just-right" model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

Fig. 1

Types of chromosomal instability. CIN is classified into numerical CIN and structural CIN. Numerical CIN corresponds to the gain or loss of whole chromosomes (aneuploidy) or gain of extra set of chromosomes (polyploidy), while structural CIN refers to the gain or loss of chromosome segments due to deletion, amplification, inversion, and translocation

Fig. 2

Timeline of key milestones in the CIN research. Green represents milestones in basic CIN research, pink represents milestones in CIN clinical translation, and blue represents milestones in CIN meta-analysis and databases

Fig. 3

Indicators of CIN. Example of indicators commonly used to assess CIN, including lagging chromosomes, chromosome bridges, micronuclei, aneuploidy, and polyploidy

Fig. 4

Causes of CIN. a Replication stress leads to stalling and collapse of replication forks, which results in DSBs. b Sister chromatid defect allows premature separation of sister chromatids before full alignment, leading to chromosome missegregation. c Aberrant centrosome number such as monopolar spindle and multipolar spindle could lead to aneuploidy. d Microtubule kinetochore attachment error causes failure to form bi-orientation, where each kinetochore is attached to microtubules from only one spindle pole, leading to chromosome missegregation. e Aberrant SAC could lead to aneuploidy, as weakened SAC causes premature chromatid separation, while hyperactivated SAC results in a lagging chromosome. f Extra set of chromosomes as seen in polyploidy could arise from cytokinesis failure, mitotic slippage, or endoreduplication

Fig. 5

CIN paradox according to the “just-right” model. A moderate, “just-right” level” for CIN could induce a tumor-promoting phenotype by increasing tumor cells adaptability, while excessive CIN is deleterious to tumor cells due to excessive chromosome gain or loss leading to cell death

Fig. 6

Consequences of CIN. a Chromothripsis, also known as “chromosome shattering” is induced from rupture of micronuclei, followed by fragmentation of micronuclear DNA and its massive rearrangements. b Protein stoichiometry imbalance caused by changes in the copy number of chromosomes, leading to proteotoxic stress. c Other cellular functions altered by CIN, including metabolic alteration, cell cycle arrest, and senescence

Fig. 7

Impact of CIN on drug resistance. CIN confer resistance to anti-tumor drug treatment or immune response through increased intratumor heterogeneity