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

Abstract

AbstractA 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 CKS1B is strongly associated with both W-CIN and S-CIN. Finally, we propose a potential copy number dependent mechanism to activate the PI3K pathway in high CIN tumours.1.Simple summaryMany cancer cells are chromosomally unstable, a phenotype describing a tendency for accumulating chromosomal aberrations. Entire chromosomes tend to be gained or lost, which is called whole chromosome instability (W-CIN). Structural chromosomal instability (S-CIN) describes an increased rate of gaining, losing or translocating smaller parts of chromosomes. Here we analyse data from 33 cancer types to find differences and commonalities between W-CIN and S-CIN. We find, that W-CIN is strongly linked to whole genome doubling (WGD), whereas S-CIN is associated with a specific DNA damage repair pathway. Both W-CIN and S-CIN are difficult to target using currently available compounds and have distinct prognostic values. The activity of the drug resistance gene CKS1B is associated with both CIN types, which merits further investigation as potential CIN target. In addition, we identify a potential copy number based mechanism promoting signalling of the important PI3K cancer pathway in high CIN tumours.