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Meta-Analysis
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Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes

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Meta-Analysis

Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes

Ninel M Vainshelbaum et al. Genes (Basel).

Abstract

Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumor types, and was especially high in seminoma. For all tumor types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state (r ≈ 0.9, p < 0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in three of the five benign tumor types, especially notable in colon adenoma. Principal component analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumor types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome (a possible mimic of the fertilization aberration, 69, XXY digyny) associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results as a secondary factor from chromosome instability.

Keywords: XXY; cancer near-triploidy; digyny; karyotype meta-analysis; male tumors; whole-genome rearrangements.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The modal chromosome number frequency histograms of 15 malignant tumor cohorts, numbered as listed in Table 1. The chromosome numbers within the (arbitrarily chosen) range of near-triploidy (62–76 chromosomes) are marked red.
Figure 1
Figure 1
The modal chromosome number frequency histograms of 15 malignant tumor cohorts, numbered as listed in Table 1. The chromosome numbers within the (arbitrarily chosen) range of near-triploidy (62–76 chromosomes) are marked red.
Figure 2
Figure 2
Results of the Pearson correlation analysis for all 15 patient karyotype cohorts of malignant tumors, evaluating the relationship between all karyotypes containing doubled X-chromosomes and ploidy in different chromosome ranges: (A) In relation to the narrow triploidy range (66–72 chromosomes); (B) in relation to the median triploidy range (62–76 chromosomes); (C) in relation to the wide (International System for Human Cytogenetic Nomenclature, ISCN) triploidy range (58–80 chromosomes); (D) in relation to the near-diploidy range (41–61 chromosomes); (E) in relation to near-tetraploidy range (77–98 chromosomes); and (F) only malignant somatic tumors are presented as related to the near-triploidy median range. The tumor cohort numbers are the same as in Table 1.
Figure 3
Figure 3
Results of the Pearson correlation analysis for malignant tumors evaluating the relationship between different karyotypes containing disomic X-chromosomes and ploidy in the median near-triploidy range. (A) For XXY and (B) XXY+(XY,+X) configurations; (C) X-disomic karyotypes with a Y chromosome; and (D) X-disomic karyotypes lacking a Y chromosome. The tumor cohort numbers are the same as in Table 1.
Figure 4
Figure 4
The percentages of different sex chromosome configurations and their respective percentages of near-triploidy (62–76 chromosomes) for all malignant tumor cohorts, numbered as listed in Table 1.
Figure 5
Figure 5
Benign tumor karyotypes. Left column: The histograms of the modal chromosome numbers, with near-triploidy marked red. Right column: The corresponding percentages of different sex chromosome configurations with #X-disomy and their respective percentages of near-triploidy (62–76 chromosomes) for five benign tumor cohorts. Designations (a,b) in the right column: (a) #X-disomic karyotypes lacking a Y chromosome (XX,-Y and X,-Y,+X); (b) #X-disomic karyotypes with a Y chromosome (XXY and XY,+X).
Figure 6
Figure 6
PCA results of the X-chromosome disomy distribution in the triploidy space for 15 malignant tumor types, designated as numbered in Table 1.
Figure 7
Figure 7
Schematic of the digyny-like formation of XXY triploid karyotypes in somatic male tumors. The reprogrammed male tumor cell triggers the aberrant molecular pathway of the pseudo-meiotic prophase from the G2-phase, undergoes recombination between cohered sisters and possibly also homologues, undergoes pseudo-meiosis I segregating maternal and paternal progenies with cohered sister chromatids, and triggers the reduction to haploidy of the “paternal gamete” in the pseudo-meiosis II and its pedogamic fusion with the unreduced diploid “maternal gamete”, resulting in triploid “digynic parthenote”.

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