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

Abstract

Stable aneuploid genomes with nonrandom numerical changes in uneven ploidy ranges define distinct subsets of hematologic malignancies and solid tumors. The idea put forward herein suggests that they emerge from interactions between diploid mitotic and G0/G1 cells, which can in a single step produce all combinations of mono-, di-, tri-, tetra- and pentasomic paternal/maternal homologue configurations that define such genomes. A nanotube-mediated influx of interphase cell cytoplasm into mitotic cells would thus be responsible for the critical nondisjunction and segregation errors by physically impeding the proper formation of the cell division machinery, whereas only a complete cell fusion can simultaneously generate pentasomies, uniparental trisomies as well as biclonal hypo- and hyperdiploid cell populations. The term “somatic sex” was devised to accentuate the similarities between germ cell and somatic cell fusions. A somatic cell fusion, in particular, recapitulates many processes that are also instrumental in the formation of an abnormal zygote that involves a diploid oocyte and a haploid sperm, which then may further develop into a digynic triploid embryo. Despite their somehow deceptive differences and consequences, the resemblance of these two routes may go far beyond of what has hitherto been appreciated. Based on the arguments put forward herein, I propose that embryonic malignancies of mesenchymal origin with these particular types of aneuploidies can thus be viewed as the kind of flawed somatic equivalent of a digynic triploid embryo.

Copy Number Changes and Allele Distribution Patterns of Chromosome 21 in B Cell Precursor Acute Lymphoblastic Leukemia

“…All variants of tetra-and pentasomies in constitutional disomic or trisomic individuals that result from a meiosis 2 or mitotic error, produce identical allele distribution patterns, in case of tetrasomies either a "2 + 2" or "3 + 1" and in case of pentasomies a "3 + 2" or "4 + 1" one. By far the vast majority of tetrasomies derive from the duplication of both parental homologues ("2 + 2") in both constitutional disomic as well as trisomic cases, whereas the alternative "3 + 1" pattern is much rarer [17,51]. The same applies also to pentasomies: a "3 + 2" is significantly more common than a "4 + 1" pattern.…”

“…A tetrasomy 21 is essentially the defining feature and diagnostic hallmark of hyperdiploid ALL forms [17,51]. The different allele distribution patterns that underlie the various kinds of tetrasomy in constitutional disomic and trisomic individuals are schematically explained in Figure 7.…”

“…There were 154 "classical" hyperdiploid cases, 145 of which had a "2 + 2", eight a "3 + 1" and one a "2 + 1 + 1" allele distribution pattern (Figures 8 and 9). In addition, there were seven cases that had either a hyperhaploid and/or a hyperdiploid clone with a genome-wide CN-LOH, which means that the respective hyperhaploid clones contained a biparental pair and the corresponding hyperdiploid versions a biparental tetrasomy of chromosome 21 [51]. Low hyperdiploid genome-wide CN-LOH cases form a unique array-definable entity.…”

“…Low hyperdiploid genome-wide CN-LOH cases form a unique array-definable entity. They have only between 48 and up to 54 chromosomes and most likely derive from a single mitotic cell in a single step rather than from the genomic duplication of an afore generated hyperhaploid cell clone [51].…”

“…Copy number validation with a RUNX1 FISH probe also uncovered small subclones with three and four chromosomes 21 in all of them. Whether these resulted from chromosome loss or, vice versa, whether pentasomy arose from successive gains remains to be seen, although one may concede that for a cell the loss of a superfluous chromosome is generally easier to cope with than acquiring an additional one [51]. The corresponding allele copy numbers are indicated below the respective STR markers.…”