Journal article
A survey of chromosomal instability measures across mechanistic models
Proceedings of the National Academy of Sciences - PNAS, Vol.121(16), pp.e2309621121-e2309621121
04/16/2024
DOI: 10.1073/pnas.2309621121
PMCID: PMC11032477
PMID: 38588415
Abstract
Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation rates remain challenging to assess in human cancer despite an array of available measures. We evaluated measures of CIN by comparing quantitative methods using specific, inducible phenotypic CIN models of chromosome bridges, pseudobipolar spindles, multipolar spindles, and polar chromosomes. For each, we measured CIN fixed and timelapse fluorescence microscopy, chromosome spreads, six-centromere FISH, bulk transcriptomics, and single-cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples significantly correlated (R = 0.72;
< 0.001) and sensitively detect CIN. Cytogenetics approaches include chromosome spreads and 6-centromere FISH, which also significantly correlate (R = 0.76;
< 0.001) but had limited sensitivity for lower rates of CIN. Bulk genomic DNA signatures and bulk transcriptomic scores, CIN70 and HET70, did not detect CIN. By contrast, scDNAseq detects CIN with high sensitivity, and significantly correlates with imaging methods (R = 0.82;
< 0.001). In summary, single-cell methods such as imaging, cytogenetics, and scDNAseq can measure CIN, with the latter being the most comprehensive method accessible to clinical samples. To facilitate the comparison of CIN rates between phenotypes and methods, we propose a standardized unit of CIN: Mis-segregations per Diploid Division. This systematic analysis of common CIN measures highlights the superiority of single-cell methods and provides guidance for measuring CIN in the clinical setting.
Details
- Title: Subtitle
- A survey of chromosomal instability measures across mechanistic models
- Creators
- Andrew R Lynch - University of Wisconsin Carbone Cancer CenterShermineh Bradford - University of Wisconsin Carbone Cancer CenterAmber S Zhou - University of Wisconsin Carbone Cancer CenterKim Oxendine - University of Wisconsin–MadisonLes Henderson - University of Wisconsin–MadisonVanessa L Horner - University of Wisconsin–MadisonBeth A Weaver - University of Wisconsin Carbone Cancer CenterMark E Burkard - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.121(16), pp.e2309621121-e2309621121
- DOI
- 10.1073/pnas.2309621121
- PMID
- 38588415
- PMCID
- PMC11032477
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Grant note
- F31 CA254247 / NCI NIH HHS S10 RR025483 / NCRR NIH HHS T32 HG002760 / NHGRI NIH HHS T32 GM008688 / NIGMS NIH HHS P30 CA014520 / NCI NIH HHS R01 CA234904 / NCI NIH HHS
- Language
- English
- Date published
- 04/16/2024
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701259502771
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