Role of chromosomal instability in cancer progression

Abstract

Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients

“…The latter patient harbored five high level of DNA coamplifications that may have a synergistic effect and be deleterious for NB cell survival, considering that this case was the only one in complete remission. It is known that elevated chromosomal instability (CIN) may surpass the threshold compatible with cell viability of tumor cells . Paradoxically, high level of CIN in cancer has been shown to impact survival outcome and with therapeutic responses improving prognosis, due to the excess of genotoxicity .…”

Chromosomal Instability in Tumor Initiation and Development

“…CIN as a prognostic tool CIN is commonly associated with tumorigenesis and clinical outcomes ( Supplementary Table S1); various reports have shown that aneuploidy that arises as a consequence of CIN in malignant tumors favors the evolution of tumors (88)(89)(90). Investigation of CIN signatures from specific genes whose expression was consistently associated with total functional aneuploidy in many different cancer types and the net overexpression of this signature were predictive of poor clinical outcome in 12 cancer data sets representing 6 cancer types (91).…”

Non-Random Mis-Segregation of Human Chromosomes

“…Aneuploidy -deviation from a multiple of the haploid chromosome number -is the leading cause of spontaneous miscarriage and birth defects in humans (Nagaoka et al, 2012) and represents a key hallmark of cancer (Mitelman) where recurrent patterns of aneuploidy, or somatic copy number alteration (SCNA) are observed (Ben-David et al, 2016;Duijf et al, 2013;Faggioli et al, 2012;Mitelman;Nagaoka et al, 2012). SCNA patterns in cancer are a consequence of 'chromosome alteration' rate driven by chromosomal instability (CIN), which is associated with poor prognosis for cancer patients Jamal-Hanjani et al, 2015;Laughney et al, 2015;Lee et al, 2011;McClelland, 2017) coupled to evolutionary selection. Human chromosomes vary widely in size, gene density, interphase nuclear territory and heterochromatin distribution (Figure 1a, Table S1).…”