Distinct and Common Features of Numerical and Structural Chromosomal Instability across Different Cancer Types.

Xiaoxiao Zhang,Maik Kschischo

doi:10.3390/cancers14061424

Abstract

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 S-CIN, which merits further investigation. In addition, we identify a potential copy number-based mechanism promoting signalling of the important PI3K cancer pathway in high-S-CIN tumours.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, but we also report compounds and drugs which should be investigated as targets for W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities with pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance gene CKS1B is strongly associated with S-CIN. Finally, we propose a potential copy number-dependent mechanism to activate the PI3K pathway in high-S-CIN tumours.

Highlights

An alternative is to use single cell analysis to quantify cell to cell karyotype heterogeneity within a population of cells. The latter approach is based on the assumption that the degree of chromosomal instability (CIN) is reflected by the degree of karyotype heterogeneity
Using an analogous separation of the tumour samples into SCSlow and SCShigh groups using the median structural complexity score (SCS) in each tumour type, we found that the overall survival of patients in 11 out of 33 cancers is negatively associated with Structural CIN (S-CIN) (Figure 2B, Table A2, log rank test, p < 0.05)
Our results suggest that whole genome doubling and homologous recombination deficiency might be the most important drivers for Whole chromosome instability (W-CIN) and S-CIN, respectively

Summary

Introduction

A large proportion of human tumours exhibits abnormal karyotypes with gains and losses of whole chromosomes or structural aberrations of parts of chromosomes [1–3]. In many cases, these karyotypic changes are the result of ongoing chromosomal instability (CIN), which is defined as an increased rate of chromosomal changes. Two major forms of CIN can be distinguished: Whole chromosome instability (W-CIN), which is called numerical CIN, refers to the ongoing acquisition of gains and losses of whole chromosomes. CIN is to be distinguished from polyploidy, where the whole set of chromosomes is increased

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