Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells

Abstract

Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 ( P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes contained in two clusters were particularly affected: the first cluster on cytoband 13q13 contained 7 highly up-regulated genes ( NBEA, MAB21L1, DCLK1, SOHLH2, CCDC169, SPG20 and CCNA1 , P = .0003) in all clones. A second cluster was located on 13q32.1 and contained five upregulated genes ( ABCC4, CLDN10, DZIP1, DNAJC3 and UGGT2, P = .003). One gene, RASL11A, localized on chromosome band 13q12.2 , escaped the copy number-induced overexpression and was reproducibly and significantly down-regulated on the mRNA and protein level ( P = .0001, FDR = 0.002). RASL11A expression levels were also lower in primary colorectal tumors as compared to matched normal mucosa ( P = .0001, FDR = 0.0001. Overexpression of RASL11A increases cell proliferation and anchorage independent growth while decreasing cell migration in +13 clones. In summary, we observed a strict correlation of genomic copy number and resident gene expression levels, and aneuploidy dependent consistent genome-wide transcriptional deregulation.

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…The conventional interpretation of the AD‐like dementia in DS patients is that it is due to the APP gene on chromosome 21; triplicate copies of the APP gene facilitate amyloid‐beta accumulation and development of AD in DS patients. Yet, aneuploidy can also produce proteotoxic effects and ER stress, and disturb stoichiometry of macromolecular complexes (Brennan et al, ; Chunduri & Storchová, ), as well as transcriptomic alterations at the cellular and/or organ level, compared with those of nonaneuploid control subjects (Wangsa et al, ). Thus, the general effects of aneuploidy at the cellular and organ levels may contribute to AD development, in addition to APP overproduction in patients with DS.…”

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

“…To achieve this, membrane fragments first coat the individual chromosomes, which only then agglomerate and coalesce into distinct nuclei again (Schooley et al, 2012). Such single chromosome micronuclei form the basis for the microcell-mediated transfer of exogenous chromosome material into host cells (Meaburn et al, 2005;Fenech et al, 2011), which even enabled the successful integration of entire intact human chromosomes 8, 13, 18 and 21 into human isogenic embryonic stem cells (Kazuki et al, 2014;Hiramatsu et al, 2019) as well as chromosomes 3, 7 and 13 into the karyotypic stable, mismatch repair deficient colorectal cancer cell line DLD-1 (Upender et al, 2004;Nicholson et al, 2015;Rutledge and Cimini, 2016;Wangsa et al, 2019). A missegregated micronucleus can also undergo massive shattering and restructuring before these pieces rejoin again and form a new single chromatid, which can then become part of the nucleus again.…”

“…The gain or loss of single and, even more so, multiple chromosomes that may even occur simultaneously, alters the expression of hundreds of genes and consequently also the intricate balance of proteins and their interactions in cellular networks (Hertzberg et al, 2007;Li et al, 2013;Ben-David et al, 2014;Durrbaum and Storchova, 2016;Antonarakis, 2017;Wangsa et al, 2019;Yang et al, 2019). For the maintenance of intracellular homeostasis such gross dysregulations pose a significant challenge.…”

Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

“…Hence, tetraploidy is likely to allow tumor cells to withstand a higher incidence of mutations, thereby increasing the probability of adaptive changes. Second, tetraploid cells have an increased rate of chromosome missegregation [31][32][33] , thus increasing the possibility that a developing tumorigenic clone will accumulate and tolerate the mutations needed for its progression to a malignant state 34 . Thirdly, proliferating tetraploid cells are genetically unstable and can facilitate tumor progression by giving rise to aneuploidy, a known hallmark of cancer 35 .…”