Genetic instability in colorectal cancers

Abstract

It has long been considered that genetic instability is an integral component of human neoplasia. In a small fraction of tumours, mismatch repair deficiency leads to a microsatellite instability at the nucleotide sequence level. In other tumours, an abnormal chromosome number (aneuploidy) has suggested an instability, but the nature and magnitude of the postulated instability is a matter of conjecture. We show here that colorectal tumours without microsatellite instability exhibit a striking defect in chromosome segregation, resulting in gains or losses in excess of 10(-2) per chromosome per generation. This form of chromosomal instability reflected a continuing cellular defect that persisted throughout the lifetime of the tumour cell and was not simply related to chromosome number. While microsatellite instability is a recessive trait, chromosomal instability appeared to be dominant. These data indicate that persistent genetic instability may be critical for the development of all colorectal cancers, and that such instability can arise through two distinct pathways.

Genetic bottlenecks and the hazardous game of population reduction in cell line based research

“…Both these models assume that the original tumour cell population has some degree of genomic instability and is therefore genetically heterogeneous, consisting of more than one sub-clone that can be defined according to its genomic profile. This is consistent with the situation found in the majority of commonly used human cell lines [4][5][6][7][8]. Under this assumption, the capacity for formation of clones with novel chromosome aberrations in vitro will depend largely on the fitness of cells having acquired novel genomic changes.…”

“…It is well known that the extent to which cancer cell lines recapitulate the features of their original tumours is highly variable with respect to morphology, gene expression, and genetic alterations [3]. Furthermore, many cell lines are derived from tumours with an inherent genomic instability [4][5][6][7][8] that may potentially lead to continuous evolution of novel genetic features during prolonged in vitro growth. Cytogenetic studies have demonstrated the presence of two stages of karyotype evolution during the establishment of cancer cell lines, an early phase characterized by cytogenetic heterogeneity and selection of clones fit for in vitro propagation, and a later phase which is relatively more stable with respect to chromosomal alterations [9].…”

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

“…In addition, the microsatellite stable (MSS) type, which is similar to CIN, is also important in colorectal carcinogenesis. Studies have shown that MSI and MSS are mutually exclusive and are also used as basic molecular classification 3, 7…”

“…However, the MSS phenotype is the main molecular phenotype in both LC and RC 10, 11. Previous reports have shown that the MSS phenotype is found in approximately 60–70% of RC and around 90% of LC 3, 7. To identify the molecular or clinicopathological differences between LC and RC, we must examine the molecular or clinicopathological differences in the MSS phenotype between LC and RC, given that the MSS phenotype is common in CRC.…”

Regulation and function of the interaction between the APC tumour suppressor protein and EB1

“…It is tempting to speculate that the loss of the interaction between APC and EB1 which occurs upon APC truncation could compromise the putative mitotic checkpoint function of EB1. This could contribute to the chromosomal instability observed in some colorectal cancer cell lines (Lengauer et al, 1997) by a failure to arrest abnormal mitoses. This intriguing hypothesis deserves further investigation.…”