Chromosomal instability and cancer: a complex relationship with therapeutic potential

Germline mutation contribution to chromosomal instability

“…CIN tumors commonly feature wide-spread changes in chromosome number also known as aneuploidy, translocations, inversions, amplifications and deletions, often involving the loss of heterozygosity (LOH) (Pino & Chung 2010, Schvartzman et al 2010, Pikor et al 2013. Populations of CIN cells with such karyotypically variable genome are capable of selective evolution and under the right conditions, can subsequently undergo clonal expansion thus driving tumor development, progression as well as acquisition of resistance to therapy (Lengauer et al 1998, Bakhoum & Compton 2012, Pikor et al 2013.…”

“…The molecular mechanisms underlying CIN has been actively investigated for years and we now know these include defects in mitotic spindle assembly checkpoint (SAC), sister chromatid cohesion, kinetochoremicrotubule attachment dynamics, cell cycle regulation, multipolar spindles as well as supernumerary centrosomes (Thompson et al 2010, Bakhoum & Compton 2012, Giam & Rancati 2015. Under normal circumstances, proper functioning of these mechanisms govern the fidelity of chromosome segregation by ensuring correct orientation of all chromosomes on the microtubule spindle for cell division and deferring progression into the anaphase stage of mitosis until the chromosomes are ready for division (Holland & Cleveland 2009, Thompson et al 2010, Bakhoum & Compton 2012.…”

“…Under normal circumstances, proper functioning of these mechanisms govern the fidelity of chromosome segregation by ensuring correct orientation of all chromosomes on the microtubule spindle for cell division and deferring progression into the anaphase stage of mitosis until the chromosomes are ready for division (Holland & Cleveland 2009, Thompson et al 2010, Bakhoum & Compton 2012. Defects in these mechanisms lead to chromosome lagging as well as premature initiation of anaphase before all the chromosomes are aligned to the spindles, leading to an increased risk of chromosome mis-segregation (Fig.…”

“…Nucleotide instability (NIN) is the increased frequency of base-pair mutations (Negrini et al 2010, Pikor et al 2013, whereas microsatellite instability (MIN) is characterized by the expansion and contraction of microsatellite sequences, usually as a consequence of defective cellular DNA mismatch repair (Boland & Goel 2010, Negrini et al 2010, Pikor et al 2013. However, the most prominent form of genomic instability in human cancers is chromosomal instability (CIN), which is the elevated rate of gain or loss of segmental or whole chromosomes, typically resulting in karyotypic heterogeneity (Negrini et al 2010, Pino & Chung 2010, Bakhoum & Compton 2012, Pikor et al 2013. Most solid tumors display some form of aneuploidy, and it has been long implicated that CIN fuels cancer development and progression (Negrini et al 2010, Bakhoum & Compton 2012.…”

“…However, the most prominent form of genomic instability in human cancers is chromosomal instability (CIN), which is the elevated rate of gain or loss of segmental or whole chromosomes, typically resulting in karyotypic heterogeneity (Negrini et al 2010, Pino & Chung 2010, Bakhoum & Compton 2012, Pikor et al 2013. Most solid tumors display some form of aneuploidy, and it has been long implicated that CIN fuels cancer development and progression (Negrini et al 2010, Bakhoum & Compton 2012.…”