Chromosomal instability, aneuploidy, and cancer.

Samuel F Bakhoum,Charles Swanton

doi:10.3389/fonc.2014.00161

Abstract

The link between aneuploidy and cancer has been recognized overa century ago (1). Abnormalities in chromosome copy numbersarise from persistent errors in chromosome segregation dur-ing cell division, a process known as chromosomal instability(CIN) (2). CIN is a principal contributor to genetic heterogene-ity in cancer (3) and is an important determinant of clinicalprognosis and therapeutic resistance (4, 5). Over the past twodecades, our understanding of the mechanisms that lead to CINas well as our appreciation of its consequences on cellular via-bility and tumor evolution have grown considerably (4, 6). Sohas our recognition of the multitude of questions that remainunanswered.The papers in this Research Topic broadly address recentadvances in our understanding of CIN in cancer. They also illus-trate the diverse experimental approaches and model organismsused in studying genomic instability. This topic is divided intotwo major categories: the ﬁrst ﬁve papers address the genesis ofCIN in cancer by summarizing the cell biological mechanisms thatunderlie chromosome missegregation. They also venture into thepoorly understood area of the genetic basis of CIN,while develop-ing an experimental model system amenable to high-throughputgenetic analysis. The remaining papers address the consequencesof imbalance in chromosome number on the cellular ﬁtness andadaptation.Multiple mechanisms have been shown to lead to CIN – inits numerical and structural forms. They include defects in thespindle assembly checkpoint (7), sister chromatid cohesion (8),the regulation of microtubule attachments to chromosomes atkinetochores (9, 10), centrosome duplication (11, 12), telom-ere maintenance (13), and pre-mitotic replication stress (14).Herein, German Pihan (15) reviews the regulation of the cen-trosome duplication cycle and how it is intricately synchronizedwith the cell division cycle. The complexity of this regulatorynetwork might explain pervasiveness of centrosome dysfunctionin human tumors, but it also provides multiple attractive phar-macological targets that have the potential to induce mitoticcatastrophe. Yokoyama and Gruss (16) further discuss how chro-mosomes take on part of the responsibility to ensure the ﬁdelity oftheir own segregation. Chromatin-associated factors – beyond theRan GTPase – have now been shown necessary for a properlyfunctioning mitotic spindle. Interestingly, many of these fac-tors localize to the Nuclear Pore Complex (NPC), highlightingan incipient spatiotemporal relationship between the interphasenuclear structure and the mitotic spindle (17). Thus the processof faithful chromosome segregation starts well before the onset ofmitosis.While many of the cellular events that underlie CIN have nowbeen uncovered, the genetic basis of chromosome missegregationand aneuploidy remains elusive. A growing number of geneticperturbations have been shown capable of inducing CIN in oth-erwise normal mammalian cell lines (6). Yet, it remains unknownwhether these experimental conditions mimic naturally occur-ring genetic events that lead to CIN during tumor progression.Further complicating this matter is the self-propagating natureof CIN (18), which can mask initial instigating genetic triggers.Herein,Rao andYamada (19) review the linear progression modelof colon carcinogenesis from adenoma to carcinoma. They dis-cuss how many of the sequential genetic events that occur dur-ing carcinogenesis have the potential to compromise the ﬁdelityof chromosome segregation. More generally, Orr and Compton(20) discuss the intimate relationship governing CIN and knownoncogenic pathways. Given what we now know, they argue thatalmost every major oncogenic pathway can be implicated in somemanner in the genesis of CIN. Yet this relationship is almostcertainly bidirectional as chromosome missegregation has beenshown to generate downstream structural chromosomal damage,whichcaninturnindependentlyactivateoncogenicpathways(21–23). This complex relationship highlights the need for appropriategenetic models to better understand CIN. To this end, Salemiet al. (24) develop a chromosome segregation error correctionassay, using the

Highlights

The papers in this Research Topic broadly address recent advances in our understanding of chromosomal instability (CIN) in cancer
The papers in this Research Topic broadly address recent advances in our understanding of CIN in cancer. They illustrate the diverse experimental approaches and model organisms used in studying genomic instability. This topic is divided into two major categories: the first five papers address the genesis of CIN in cancer by summarizing the cell biological mechanisms that underlie chromosome missegregation
Rao and Yamada [19] review the linear progression model of colon carcinogenesis from adenoma to carcinoma. They discuss how many of the sequential genetic events that occur during carcinogenesis have the potential to compromise the fidelity of chromosome segregation

Summary

Introduction

This topic is divided into two major categories: the first five papers address the genesis of CIN in cancer by summarizing the cell biological mechanisms that underlie chromosome missegregation. The remaining papers address the consequences of imbalance in chromosome number on the cellular fitness and adaptation. While many of the cellular events that underlie CIN have been uncovered, the genetic basis of chromosome missegregation and aneuploidy remains elusive.

Results

Conclusion