Single-cell whole genome sequencing (scWGS) applied to chromosome instable lymphoma samples reveals high levels of copy number heterogeneity between individual cells, indicating ongoing chromosome instability despite the presence of recurrent clonal chromosome copy number states detectable by bulk measurement. This cell-to-cell variability in chromosome numbers demonstrates that chromosomal instability continues to generate karyotype diversity within tumors. [@bakker_single-cell_2016]
Definitions
Synthesis
Single-cell sequencing reveals that chromosomally unstable lymphomas exhibit convergent karyotypic evolution, with recurrent and clonal gains of specific chromosomes emerging from ongoing chromosomal instability that is counterbalanced by selective pressures favoring particular copy number states. The underlying mechanistic relationship involves chromosomal instability generating immune cell infiltration into tumors, which creates a fitness cost that aneuploid cancer cells overcome by specifically inactivating Stat1 signaling combined with increased Myc activity, thereby suppressing immune surveillance while adapting to aneuploidy-induced stress. This immune evasion mechanism is conserved between mouse and human aneuploid cancers, distinguishing chromosomally unstable tumors from those with p53 loss alone, which is common but not specifically enriched in this tumor subset. What remains contested is the broader paradox of aneuploidy’s dual roles, as elevated chromosomal instability drives spontaneous tumor formation in aged animals yet simultaneously inhibits chemically or genetically induced tumorigenesis, suggesting that context-dependent factors determine whether karyotypic heterogeneity promotes or suppresses malignant transformation.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Mps1 truncation-induced CIN generates convergent recurrent chromosome gains
- Chromosomal instability promotes immune cell infiltration into tumors
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploid cancers inactivate Stat1 to circumvent immune surveillance
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Extra centrosomes correlate with chromosomal instability in tumors
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- CIN exists independently of classic mitotic defects in most cells
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- p53 loss is common but not enriched in chromosomally unstable tumors
- CENP-E reduction generates aneuploidy and chromosomal instability
- Missegregation alone insufficient for aneuploid cell propagation