Distinct and common features of numerical and structural chromosomal instability across different cancer types

A large proportion of tumours is characterised by numerical or structural chromosomal instability (CIN), defined as an increased rate of gaining or losing whole chromosomes (W-CIN) or of accumulating structural aberrations (S-CIN). Both W-CIN and S-CIN are associated with tumourigenesis, cancer progression, treatment resistance and clinical outcome. Although W-CIN and S-CIN can co-occur, they are initiated by different molecular events. By analysing tumour genomic data from 33 cancer types, we show that the majority of tumours with high levels of W-CIN underwent whole genome doubling, whereas S-CIN levels are strongly associated with homologous recombination deficiency. Both CIN phenotypes are prognostic in several cancer types. Most drugs are less efficient in high CIN cell lines, we also report compounds and drugs which could specifically target W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities at pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance gene \textit{CKS1B} is strongly associated with both W-CIN and S-CIN. Finally, we propose a potential copy number dependent mechanism to activate the \textit{PI3K} pathway in high CIN tumours.

Distinct and common features of numerical and structural chromosomal instability across different cancer types

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