Marked aneuploidy and loss of multiple chromosomes are common in autosomal mutants isolated from normal mouse kidney epithelium

Abstract

Marked aneuploidy and loss of multiple chromosomes are hallmarks of cancer, but whether these events are only present in malignant cells is not known. In prior work, we showed that approximately half of spontaneous autosomal mutants isolated directly from normal kidney epithelium arose from loss of a marker chromosome 8 containing the wild type Aprt gene. Chromosome loss was detected by loss of heterozygosity (LOH) for all chromosome 8 polymorphic loci examined (Turker et al, Aging Cell, 6:73-86, 2007). To determine whether loss of chromosome 8 reflected a larger mitotic event, LOH was examined for polymorphic loci on 11 non-selected chromosomes in Aprt mutants that lost the selected chromosome 8 homologue. LOH events were detected for one or more non-selected chromosomes in 38% of these mutants. The additional LOH events also reflected apparent chromosome loss based on the molecular analysis. Metaphase spreads from mutants that lost chromosome 8 were markedly aneuploid and chromosome painting revealed reduced levels for any chromosome shown to be lost with the LOH analysis. In contrast, LOH on non-selected chromosomes was infrequent in Aprt mutants exhibiting intragenic events or mitotic recombination for chromosome 8, and marked aneuploidy was absent. These observations suggest that the mechanism leading to chromosome loss in somatic mammalian cells is often not a simple non-disjunction event and instead could result from a single catastrophic event. They also suggest that cells with characteristics of malignancy are present in normal appearing tissue.

Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change

“…We use the term “genomic LOH” to describe these mutants. Here we examined genomic LOH in the clonally derived Aprt kidney mutants isolated from the mice exposed to 0.25, 0.5, 1.0, or 2.0 Gy Fe ions using a set of polymorphic loci from 11 chromosome pairs [ 33 ]. When we scored the percentage of all Aprt mutants isolated from Fe ion exposed kidneys (i.e., pooling data from mutants isolated at all four doses) that exhibit LOH for one or more of these polymorphic loci for the exposed groups relative to the spontaneous mutants, a significant difference was observed (p = 0.001)( Fig 5A ) ( Table 4 ), though individual analyses showed significant differences only for the 1.0 (p = .009) and 2.0 Gy (p < .001) samples.…”

“…In previous work with spontaneous mutants, we showed that loss of chromosome 8 in an un-irradiated tissue is predictive of, and presumably mechanistically linked to, loss of other chromosomes [ 33 ]. Thus, the vast majority of spontaneous Aprt mutants exhibiting genomic LOH are in the subset that also lost chromosome 8.…”

“…The demonstration of a radiation effect, however, is complicated by the observation that genomic LOH is common in a subset of spontaneous Aprt kidney mutants isolated from unirradiated kidneys; specifically those that lost Aprt expression due to loss of chromosome 8. The proposed explanation for this class of spontaneous mutants is that loss of multiple chromosomes is common in near tetraploid cells [ 33 ], which are relatively common in the mouse kidney (~ 10% of all cells; unpublished observation). In contrast, genomic LOH is far less common in spontaneous Aprt mutants that lose Aprt expression via other mutational events on chromosome 8 (e.g., mitotic recombination and intragenic events) (See Fig 5B ).…”

Mifepristone inhibits non-small cell lung carcinoma cellular escape from DNA damaging cisplatin

“…This suggest that MF could inhibit the ability of giant polyploid cells to give rise to diploid or paradiploid cells of normal replicative capacity, and/or cause these cells to die. Ploidy reversal, observed in vivo and in vitro [ 43 ], is a biological phenomenon not only occurring in cells in response to cytotoxic agents [ 44 ], but also during organ development [ 45 ] and tissue regeneration [ 46 ]. Cumulatively, this data suggest that MF could inhibit repopulation of NSCLC cells escaping treatment with CDDP by blocking reverse ploidy.…”

Carcinogenesis as the Sum of Its Parts

“…68 Regardless, even with a sudden arrival of a potent oncogenic mutation, cancer development is still a multistep process that requires other environmental factors and time.…”