Loss of Chromosomal Integrity in Neoplasia

Tlsty, Thea D.; Jonczyk, Piotr; White, Ayla O.; Sage, Marijke; Hall, Ingrid J.; Schaefer, Daniel J.; Briot, Amy; Livanos, Elizabeth; Roelofs, Helene; Poulose, B.; Sánchez, J.M. Martinón

doi:10.1101/sqb.1993.058.01.072

Cited by 14 publications

(7 citation statements)

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“…This has been supported, in the past, by the in vitro-derived notion that permissiveness for ampli®cation requires the disruption of several checkpoint mechanisms, often a hallmark of transformed cells. However, recent studies suggest that disruption of speci®c genes in untransformed cells can make cell permissive for gene ampli®cation and that this can occur prior to immortalization (Tlsty et al, 1993;Tainsky et al, 1995). It is therefore possible that cells exposed to continued carcinogen insult might be more susceptible to the accumulation of genetic damage and therefore may acquire the competence for gene ampli®cation prior to developing a full tumorigenic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

et al. 1998

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Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Ampli®cation of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of¯uorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of ampli®cation at the 11q13 band, we analysed 46 para n-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 ampli®ed cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene ampli®cation in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 ampli®ed tumors and ®ve of the 13 (38.4%) nonampli®ed tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 ampli®ed tumors, and it appeared to precede cyclin D1 gene ampli®cation. In contrast no dysregulated expression was detected in the premalignant lesions of the non-ampli®ed tumors. In conclusion, these ®ndings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene ampli®cation.

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Section: Discussionmentioning

confidence: 99%

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

et al. 1998

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“…Extensive diversity is often observed in neoplastic tissue. Mammalian cells possess effective control mechanisms for maintaining genomic integrity that are abrogated during tumor development (Di Leonardo et al 1993;Tlsty et al 1993). The genetic instability that tumorigenic cells often demonstrate is manifested in chromosomal rearrangements: translocations, insertions, amplifications, loss of heterozygosity and deletions.…”

Section: Introductionmentioning

confidence: 99%

Topography of genetic loci in the nuclei of cells of colorectal carcinoma and adjacent tissue of colonic epithelium

Lukášová¹,

Kozubek²,

Falk³

et al. 2004

Chromosoma

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To determine the influence of increased gene expression and amplification in colorectal carcinoma on chromatin structure, the nuclear distances between pairs of bacterial artificial chromosome (BAC) clones with genomic separation from 800 to 29,000 kb were measured and compared between the tumor and parallel epithelial cells of six patients. The nuclear distances were measured between the loci in chromosomal bands 7p22.3-7p21.3; 7q35-7q36.3; 11p15.5-11p15.4; 20p13; 20p12.2; 20q11.21 and 20q12 where increased expression had been found in all types of colorectal carcinoma. The loci were visualized by three-dimensional fluorescence in situ hybridization using 22 BAC clones. Our results show that for short genomic separations, mean nuclear distance increases linearly with increased genomic separation. The results for some pairs of loci fell outside this linear slope, indicating the existence of different levels of chromatin folding. For the same genomic separations the nuclear distances were frequently shorter for tumor as compared with epithelial cells. Above the initial growing phase of the nuclear distances, a plateau phase was observed in both cell types where the increase in genomic separation was not accompanied by an increase in nuclear distance. The ratio of the mean nuclear distances between the corresponding loci in tumor and epithelium cells decreases with increasing amplification of loci. Our results further show that the large-scale chromatin folding might differ for specific regions of chromosomes and that it is basically preserved in tumor cells in spite of the amplification of many loci.

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“…In addition to the role of p53 in growth control, p53 appears to regulate genetic stability, demonstrated by at least three dierent phenomena: allelic loss (Kinzler and Vogelstein, 1994) chromosome stability (Tlsty et al, 1993) and ploidy control (Cross et al, 1995). Another feature restricted to tumor cells and cells lacking functional p53 is gene ampli®cation (Livingstone et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of p53 results in high rates of homologous recombination

Mekeel¹,

Tang²,

Kachnic³

et al. 1997

Oncogene

209

148

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Using a plasmid substrate which integrates into the genome, we determined that the rate of homologous recombination was suppressed by p53. Human tumor cell lines, mutant or null for p53 had recombination rates 10 000-times greater than primary ®broblasts. When isogenic cell pairs from tumor cells or primary ®broblasts were compared, diering only in one genetic change which inactivated p53, the recombination rate increased 4100-fold. Functional inactivation of p53 by dominant mutant p53, by large T antigen of SV40 virus, by E6 protein of human papilloma virus, or by genetic deletion led to the same result. Our results suggest that p53 suppresses spontaneous homologous recombination, and that p53 is not required for recombination to proceed. The mechanism of recombination suppression may be related to the reported association of p53 with Rad 51, but the functional consequences of this association are not yet established. It is suggested that suppression of homologous recombination is the means by which p53 maintains genetic stability.

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Loss of Chromosomal Integrity in Neoplasia

Cited by 14 publications

References 0 publications

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

Topography of genetic loci in the nuclei of cells of colorectal carcinoma and adjacent tissue of colonic epithelium

Inactivation of p53 results in high rates of homologous recombination

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