Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53

Abstract

Fourteen colorectal cancer cell lines, categorized according to the presence or absence of microsatellite instability, were further analysed for chromosomal stability by karyotyping. NonRER (microsatellite stable) cell lines typically displayed highly aberrant karyotypes with alterations not only of chromosome number but also of chromosome structure including chromosomal deletions, inversions, and translocations. RER (microsatellite unstable) cell lines, in contrast, displayed significantly fewer alterations of chromosome number. Moreover, RER cell lines also displayed significantly fewer cytogenetically evident alterations of chromosome structure. Compared to NonRER colon cancers, RER colon cancers are significantly less likely to have undergone chromosomal gain, loss, or breakage. Characterization of p53 gene status by gene sequencing was performed in an attempt to determine if p53 gene status correlated with the chromosomal stability of the RER cancers. Gene mutations in p53 were present in all of the NonRER colon cancers. However, p53 gene mutations were also found present in four of nine of the RER colon cancers. Unexpectedly, RER colon cancers bearing mutant p53 demonstrated the same stability of chromosome number, and the same stability of chromosome structure, as the RER colon cancers with wild-type p53. Therefore, in RER colon cancers specific p53 independent mechanisms actively maintain the stability of both chromosome number and structure.

p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

“…Six (55%) of 11 G:C-to-A:T transitions occurred at CpG dinucleotides in five hot-spot codons (175, 245, 248, 273, and 282), and it was suggested that specific p53 mutations participate in the progression of human prostate cancer and may be predictive of metastasis (10). This study, in addition to some other recent studies (both in vitro and in vivo), has demonstrated correlation between loss or mutation of p53 and the presence of CI (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). More recently, centrosome hyperamplification was found to be the major mechanism responsible for CI in vitro and in vivo (58, 59, 64 -66).…”

“…A very strong correlation has been found between p53 loss or mutation and centrosome hyperamplification (27,55,59,67). Breast carcinoma and squamous cell carcinoma of the head and neck with either p53 deletion or mutation show centrosome hyperamplification (58,64,65).…”

Loss of Mitotic Spindle Checkpoint Activity Predisposes to Chromosomal Instability at Early Stages of Fibrosarcoma Development

“…10 p53 inactivation by dominant-negative mutation or germline inactivation is sufficient to achieve polyploidy in mouse cells, 20,33 However, during fibrosarcoma development, p53 mutation does not correlate with mitotic checkpoint inactivation. In this respect, some cancer cell lines with p53 mutations are diploid and chromosomally stable, 34 suggesting that p53 is unlikely to be generally responsible for chromosomal instability. In addition, disruption of p53 in two different human cell lines by gene targeting did not cause development of aneuploidy.…”

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

“…Previous studies have suggested that loss of p53 function is associated with chromosomal instability, favouring the development of aneuploidy, polyploidy, chromosomal breaks and ampli®cation (Bischo et al, 1990;Bou er et al, 1995;Carder et al, 1993;Donehower et al, 1995;Fukasawa et al, 1997;Harvey et al, 1993;Livingstone et al, 1992;Meling et al, 1993;Purdie et al, 1994;Tsukada et al, 1993;Yin et al, 1992). However, studies in a series of colorectal carcinoma cell lines by others, and sporadic colorectal cancers by us, suggest that, even in the presence of p53 mutation, MSI-H tumours remain chromosomal stable and near-diploid, rather than developing the multiple errors in chromosome number and structure shown typically by sporadic colorectal tumours without microsatellite instability (Eshleman et al, 1998;Curtis et al, 2000). In contrast, we have shown that MSI-H glioblastomas typically develop chromosomal instability and aneuploidy accompanying p53 mutation.…”