Meta-Analysis of Cancer Triploidy: Whole-Genome Rearrangements in Male Human Tumours Are Characterised by XXY Karyotypes

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. malignant and 5 benign tumour cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing the triploid fraction was observed in all malignant tumour types, being especially high in seminoma. For all tumour types, X XXY, correlated strongly with near-diploidy, and did not correlate with near component with a doubled X especially notable in colon adenoma. Principal Component Analysis revealed a non random correlation structure shaping the X 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-

When Three Isn’t a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers

“…Analysis of histograms of modal chromosome numbers in large 15 cohorts of monoclonal tumor types from the Mitelman database presented in [10] revealed near-diploid, near-triploid, and also near-tetraploid karyotypes in each tumor type. One can suggest that “monoclonal” near-triploid tumors could contain or give rise to a small amount of diploid and tetraploid sub-clones (which may be hidden in a dormant state).…”

“…From the study of 15 male malignant tumor types with near-triploid XXY karyotypes assembled from the Mitelman karyotype database presented in the accompanying paper [10] and DNA cytometry of resistant triploid breast cancer, we suggested the association of the near-triploid XXY karyotypes (XXX for females) with a digyny-like pedogamic process—somewhat like an aberrant unisexual “fertilization”. From the literature analysis and experimental evidence presented here the whole process can be deduced as follows (Figure 5).…”

“…The in-silico study of the Mitelman database was performed as described in the accompanying article [10,11]. Nota bene : For the sex chromosomes, chromothripsis was specifically filtered out by our bioinformatic pipeline, to allow us to document whole genome rearrangements [10].…”

“…Moreover, many established tumor cell lines used as models for cancer research or pharmacological studies exhibit near-triploidy [6] and many chemotherapy-resistant cancers display it in vivo [7,8,9]. In the accompanying article [10] we recently presented data for the origin of tumor triploidy based on the in silico meta-analysis of 2928 karyotypes from 15 malignant solid tumor types of male patients from the Mitelman database [11]. We provided evidence that triploidy very likely initially occurs through whole genome rearrangements when one paternal genome is added to two copies of the maternal genome (XXY karyotype correlating with near-triploidy, r = 0.88, p < 0.001).…”

“…[9,13]. For human karyotypes, near-triploidy is defined from the modal chromosome number, close to 3n = 69 chromosomes [10]. The confidence interval is chosen depending on the research object, method precision, and tasks.…”