Abstract
BackgroundChromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation.ResultsTo distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single-cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers.ConclusionOur data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0971-7) contains supplementary material, which is available to authorized users.
Highlights
Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers
When we analysed the average chromosome content in the emerging T cell acute lymphoblastic lymphomas (T-ALLs) by array comparative genomic hybridisation, we found that all lymphomas displayed highly similar karyotypes, suggesting clonal selection for the recurring chromosomal abnormalities [15]
Chromosomal instable T-ALLs show recurrent chromosome copy number changes We previously reported that Chromosomal instability (CIN) in T-cells induced by a truncation of the spindle assembly checkpoint (SAC) kinase Mps1 synergises with p53 loss in lymphomagenesis [15]
Summary
Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation. When we analysed the average chromosome content in the emerging T cell acute lymphoblastic lymphomas (T-ALLs) by array comparative genomic hybridisation (aCGH), we found that all lymphomas displayed highly similar karyotypes, suggesting clonal selection for the recurring chromosomal abnormalities [15]. Most forms of aneuploidy are expected to decrease fitness, karyotype heterogeneity could result in selection of cells that have accumulated favourable copy numbers of chromosomes expressing genes important for tumour evolution and overall cellular fitness
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