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

Abstract

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.

Single-cell omics: A new direction for functional genetic research in human diseases and animal models

“…Single-cell omics are needed to characterize these reorganized karyotypes. Methods are also required to convert the sequence data into cytogenetic data ( Zhang and Kschischo, 2022 ). Tang et al recently developed a single-cell genome sequencing method based on the third-generation sequencing (TGS) platform, called SMOOTH-seq (single-molecule real-time sequencing of long fragments amplified through transposon insertion).…”

The progress in our understanding of CIN in breast cancer research

“…Despite their apparently distinct mechanism, it is worth mentioning that both NCIN and SCIN often coexist in tumors ( 7 ). NCIN can induce SCIN and vice versa ( 22 ). In addition, the two types of CIN also have different consequences ( 23 ).…”

“…For example, NCIN often leads to DNA damage and p53 activation, while SCIN often leads to chromothripsis etc, which further aggravate GI ( 7 ). In terms of drug therapy, SCIN is more sensitive to chemotherapy and prone to drug resistance to afatinib, lapatinib and austocystin D, while NCIN is more sensitive to radiotherapy and prone to drug resistance to BRAF inhibitors ( 22 ). The differences in various aspects between these two types of CIN suggest that it is necessary to refine CIN.…”

Molecular mechanisms of replication stress-induced mitotic chromosome missegregation

“…Oncogene activation, through genetic changes such as mutations or copy number gains (Vogelstein et al, 2004;Albertson et al, 2003) causing genome instability is an early driver of tumorigenesis (Kotsantis et al, 2018). In fact, it was reported that copy number gains of several oncogenes such as MYC or CCNE1 (encoding Cyclin E) are frequently detected in chromosomally unstable cancer cell lines (Berg et al, 2017;Davoli et al, 2013;Habermann et al, 2010;Simone et al, 2002;Zhang and Kschischo, 2022). Overexpression of MYC or CCNE1 were described to cause mitotic spindle assembly defects by deregulation of microtubule organization and chromosome alignment defects resulting in aneuploidy (Keck et al, 2007;Rohrberg et al, 2020).…”