ARTICLE | doi:10.20944/preprints201904.0085.v2
Subject: Life Sciences, Cell & Developmental Biology Keywords: cancer near-triploidy; male tumours; karyotype meta-analysis; XXY; whole genome rearrangements; digyny
Online: 14 July 2019 (09:25:18 CEST)
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 5 benign tumour 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 tumour types, being especially high in seminoma. For all tumour 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 3 of 5 benign tumour types, especially notable in colon adenoma. Principal Component Analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumour 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 secondary from chromosome instability.
ARTICLE | doi:10.20944/preprints201901.0064.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: cancer; aneuploidy; meio-mitosis; disabled spindle; autokaryogamy; somatic pairing; recombination on kinetochores; reduction; chromothripsis; cleavage embryo
Online: 8 January 2019 (11:22:11 CET)
Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or with radial cytotomy including pedogamic exchanges) and release of secondary cells and/or formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle and meiotic SC checkpoints. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.
ARTICLE | doi:10.20944/preprints202005.0248.v1
Subject: Life Sciences, Biophysics Keywords: cancer; differentiation commitment; acridine-orange-DNA test; pericentromere-associated domains (PADs); power law of PAD number vs. size; critical self-organisation; unravelling of PADs; silencing threshold
Online: 15 May 2020 (08:01:08 CEST)
Finding out how cells with the same genome change fates in differentiation commitment is a challenge of biology. We used MCF-7 breast cancer cells treated with the ErbB2 ligand heregulin (HRG), which induces differentiation, to address if and how the constitutive pericentromere-associated domains (PADs) may be involved in this process. PAD-specific repressive heterochromatin (H3K9me3) and active euchromatin (H3K4me3) marking, centromere (CENPA) labelling, qPCR, acridine-orange-DNA structural test, and microscopic image analysis were applied. We found a two-step DNA unfolding, at 15-20 min and 60 min after HRG treatment, coinciding with bi-phasic activation of the early response genes (c-FOS family) and two steps of critical phase transition which were revealed in transcriptome studies. In control, the distribution of PAD number and size displays a power-law scaling with a boundary at the nucleolus. PADs’ clustering correlates with centromere numbers. 15 min after HRG treatment, the unravelling of PADs occurs, coinciding with the first step of euchromatin unfolding. The second step is associated with transcription of long-non-coding-RNA from satellite III DNA. We hypothesize that splitting of the PAD clusters under the critical size threshold of the silencing domain abrupts position effect variegation. It allows the first genome transcription avalanche to occur, starting differentiation commitment.