Cancer chromosomal instability: therapeutic and diagnostic challenges

Abstract

Chromosomal instability (CIN)-which is a high rate of loss or gain of whole or parts of chromosomes-is a characteristic of most human cancers and a cause of tumour aneuploidy and intra-tumour heterogeneity. CIN is associated with poor patient outcome and drug resistance, which could be mediated by evolutionary adaptation fostered by intra-tumour heterogeneity. In this review, we discuss the clinical consequences of CIN and the challenges inherent to its measurement in tumour specimens. The relationship between CIN and prognosis supports assessment of CIN status in the clinical setting and suggests that stratifying tumours according to levels of CIN could facilitate clinical risk assessment.

Figure 1

Numerical and structural chromosomal instability. Scheme showing whole chromosome gains and losses (numerical CIN) and sub-chromosomal gains, losses, inversions and translocations (structural CIN).

Figure 2

Mechanisms of chromosome missegregation in mitosis. (A) A wild-type division, producing identical daughter cells. (B–E) Mitotic errors that result in aneuploid daughter cells.

Figure 3

Direct methods to assess tumour CIN status. (A) Section from a renal cell carcinoma biopsy, hybridized to two fluorescently labelled centromere probes—chromosome 2 (green) and chromosome 15 (red). Variation in centromere copy number is evident between the nuclei. (B) DNA image cytometry profile for a diploid tumour (diploid DNA content determined relative to control diploid cells). (C) DNA image cytometry profile for an aneuploid tumour (determined relative to control diploid cells).

Nicholas McGranahan

Rebecca A Burrell

David Endesfelder

Marco R Novelli

Charles Swanton