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

Triploidy in cancer is associated with poor prognosis but its origins remain unclear. Here, based on frequent X-chromosome doubling in male tumours we attempted to differentiate between a random chromosomal origin and whole-genome origin 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 modal chromosome numbers (ploidy) and combinations of sex chromosomes. Karyotype heterogeneity with a distinct near-triploid fraction was observed in all malignant tumour types, especially high in seminoma. For all tumour types, X-chromosome doubling, dominantly presented by XXY, strongly correlated with the near-triploid state (r≈0.9, p<0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. The proportion of XX,-Y near-triploid karyotypes was variably increased in somatic tumours. 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. We conclude that doubling of the maternal genome followed by fusion with a paternal genome (similar to digyny) is likely responsible for the observed whole genome triploidy and may be causative for cancer initiation. The Y-chromosome may subsequently be lost due to secondary chromosome instability processes.