The Principles of Clinical Cytogenetics - Extra Materials - Springer

Chromosome Instability 347
INTRODUCTION
From: The Principles of Clinical Cytogenetics, Second Edition
Edited by: S. L. Gersen and M. B. Keagle © Humana Press Inc., Totowa, NJ
347
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Chromosome Instability
Xiao-Xiang Zhang, MD, PhD
Two levels of genetic instability have recently been characterized in human cancers: subtle
sequence changes observed at the nucleotide level and instability that is visible at the chromosomal
level (1). The high incidence of chromosome instability reported in neoplastic processes has once
again made this an area of active investigation.
Chromosome instability describes a variety of chromosome alterations, including numerical and
structural chromosomal rearrangements observed at an increased rate when compared with normal
controls. Numerical changes can be the consequence of abnormal segregation at the metaphase/
anaphase transition. Dysregulation of genes involved in chromosome condensation, sister chromatid
cohesion, kinetochore structure and function, and centrosome/microtubule formation and dynamics,
as well as cell cycle checkpoint genes has been implicated in the formation of aneuploidy, hypodiploidy,
and polyploidy. Chromosome breaks and telomere dysfunction can result in various structural
rearrangements (deletions, duplications, inversions, insertions, and translocations). Impairment of
DNA repair, DNA replication, or DNA recombination is responsible for causing sister chromatid
exchanges, fragile sites, chromatid/chromosome breaks, and mutagen sensitivity.
The most common forms of chromosome instability are seen in cancers. Virtually all malignant
human tumors contain chromosome rearrangements and, in many instances, these chromosomal
changes were considered to have occurred in the late stages of tumorigenesis. However, recent evidence
has suggested that chromosome instability was present in premalignant head and neck lesions
and that high levels of such instability were associated with subsequent tumor progression (2).
The acquisition of chromosome abnormalities by target cells is a central event that contributes to
malignant transformation and tumor development (see Chapter 16). In this chapter, we will focus on
the other forms of chromosome instability: fragile sites and chromosome breakage associated with
chromosome instability syndromes.
FRAGILE SITES IN HUMANS
Definition and Classification
Chromosomal fragile sites are specific chromosome loci that usually appear as nonstaining gaps
and breaks on metaphase preparations, either spontaneously or in response to special agents or tissue
culture conditions (see Fig. 1). All fragile sites are part of the chromosome structure and are inherited
as Mendelian codominant traits.
Fragile sites are grouped into two classes: rare and common, based on their frequency of occurrence
and means of induction. The common fragile sites are expressed in all individuals at various
rates. The most frequently observed common fragile sites occur, in decreasing order, at 3p14.2