Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

Abstract

Copy number alterations (CNAs), resulting from the gain or loss of genetic material from as little as 50 base pairs or as big as entire chromosome(s), have been associated with many congenital diseases, de novo syndromes and cancer. It is established that CNAs disturb the dosage of genomic regions including enhancers/promoters, long non-coding RNA and gene(s) among others, ultimately leading to an altered balance of key cellular functions. In cancer, CNAs have been associated with almost all steps of the disease: predisposition, initiation, development, maintenance, response to treatment, resistance, and relapse. Therefore, understanding how specific CNAs contribute to tumourigenesis may provide prognostic insight and ultimately lead to the development of new therapeutic approaches to improve patient outcomes. In this review, we provide a snapshot of what is currently known about CNAs and cancer, incorporating topics regarding their detection, clinical impact, origin, and nature, and discuss the integration of innovative genetic engineering strategies, to highlight the potential for targeting CNAs using novel, dosage-sensitive and less toxic therapies for CNA-driven cancer.

Keywords: cancer; genetic; prognostic; targeted therapy.

Figure 1

Main methods of detection of copy number alterations/variations. Timeline of the development of methods for detection of CNA/CNV, spanning from the 1970s to the present. Fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), quantitative polymerase chain reaction (qPCR), quantitative multiplex PCR of short fluorescent fragments (QMPSF), multiplex amplifiable probe hybridisation (MAPH), multiplex ligation-dependent probe amplification (MLPA), digital droplet PCR (ddPCR), next-generation sequencing (NGS) and optical genome mapping (OGM). Created with BioRender.com (accessed on 21 May 2024).

Figure 2

Mechanisms of formation of copy number alterations. Aneuploidies: (A) Chromosomes align during metaphase, followed by mis-segregation at anaphase that may lead to gain (trisomy) or loss (monosomy) of one chromosome. (B) Hypothetical mechanisms leading to hyperdiploidy and hypodiploidy due to mis-segregation of several chromosomes during anaphase. Rearrangements: (C) Amplification of genomic regions by a breakage–fusion bridge (BFB); several sequential BFB cycles can happen. (D) Chromothripsis is a catastrophic event that usually starts with BFB cycle(s), followed by the ‘explosion’ of an unstable rearranged chromosome and reintegration of DNA fragments prior to stabilisation. This process can lead to homogeneously staining regions/intrachromosomal amplification (HSR/iAMP), ring chromosomes and extrachromosomal DNA (ecDNA). (E) Extrachromosomal circular DNA occurs when a DNA fragment is excised and circularised; or following chromosomal rearrangements such as chromothripsis. (F) In deletions, genomic regions are lost mostly due to DNA double-strand breaks and non-homologous repair. (G) Duplication results from the exchange of homologous genomic segments between sister chromosomes. Dotted line represents DNA-strand breaks. Created with BioRender.com (accessed on 21 May 2024).

Figure 3

Dosage sensitivity and tumourigenesis. (A) Disomic cells have the right dosage of tumour-suppressing and tumour-promoting genes (or regulatory elements) to maintain cellular homeostasis. (B,C) Two examples of trisomic cells with different scenarios of genes/regulatory elements expressed (solid) versus not expressed (dashed) that may protect, not affect (balanced) or promote tumourigenesis in different tissues. Created with BioRender.com (accessed on 21 May 2024).