Processes shaping cancer genomes – From mitotic defects to chromosomal rearrangements

Abstract

Sequencing of cancer genomes revealed a rich landscape of somatic single nucleotide variants, structural changes of chromosomes, as well as chromosomal copy number alterations. These chromosome changes are highly variable, and simple translocations, deletions or duplications have been identified, as well as complex events that likely arise through activity of several interconnected processes. Comparison of the cancer genome sequencing data with our knowledge about processes important for maintenance of genome stability, namely DNA replication, repair and chromosome segregation, provides insights into the mechanisms that may give rise to complex chromosomal patterns, such as chromothripsis, a complex form of multiple focal chromosome rearrangements. In addition, observations gained from model systems that recapitulate the rearrangements patterns under defined experimental conditions suggest that mitotic errors and defective DNA replication and repair contribute to their formation. Here, we review the molecular mechanisms that contribute to formation of chromosomal aberrations observed in cancer genomes.

Introduction

It has long been recognized that acquired mutations and a loss of genomic integrity are key contributors to malignant growth of cancerous cells. Indeed, cancer development is driven by genomic changes leading to inactivation of tumor suppressors or the amplification and/or activation of oncogenes [1]. Additionally, as proposed more than a hundred years ago by David Hansemann and Theodore Boveri, and supported by recent discoveries, aberrant chromosomal numbers are frequent in cancer and contribute to tumorigenesis [2]. Recent enormous progress of sequencing techniques (Box 1) and large collaborative sequencing efforts, such as The Cancer Genome Atlas (TCGA) or the Pan-Cancer Analysis of Whole Genomes (PCAWG) expanded and refined the idea by revealing the complexity of cancer genomes [3]. Genomic rearrangements found in cancers are markedly variable, covering from at least 50 nucleotides to megabase-sized or even chromosome-size changes. Typically, researchers distinguish between structural and numerical aneuploidy, both being states of an abnormal chromosome set. While numerical aneuploidy defines whole chromosomal and arm-level changes, structural aneuploidy refers to subchromosomal aberrations. Individual cancer genomes often present a diverse set of genomic changes, ranging from simple translocations to highly complex structural aberrations that arise from a burst of genomic instability via numerous DNA breaks and their repair (Fig. 1) [4,5]. These aberrations often occur in a context of chromosomal instability (CIN), which is an increase in rate of gaining and losing whole chromosomes (W-CIN) or their structural fragments (S-CIN). Together, these processes affect gene copy number (CN), gene function and regulation, or may lead to a formation of oncogenic fusion-proteins [6]. The burden of somatic mutations in cancer genomes is considerable, as most tumors carry hundreds to thousands of point mutations and multiple structural and numerical chromosomal changes, depending on the tumor type [4].

The broad spectra of genomic changes raise the questions about the mechanisms responsible for chromosomal rearrangements in cancer. Experiments in model organisms from budding yeasts to human cell lines combined with advanced analysis of DNA sequence signatures provide ample evidence that exposure to genotoxic agents as well as erroneous repair of exogenous and endogenous DNA damage is the main source of genetic changes driving tumorigenesis [7]. Surprisingly, endogenous DNA damage may also result from mitotic errors, leading to massive chromosomal rearrangements [8,9]. These findings point out that structural and numerical aberrations may be more intimately linked than previously thought [10]. In this review, we will focus on mitotic errors and DNA replication and repair processes that contribute to chromosomal rearrangements in cancers, with a special focus on the formation of chromothripsis.