TP53 Abnormalities and Genetic Instability in Breast Cancer

Eyfjörd, Jórunn E.; Thorlacius, Steinunn; Valgardsdóttir, Rut; Grétarsdóttir, Sólveig; Steinarsdóttir, Margrét; Anamthawat‐Jónsson, Kesara

doi:10.3109/02841869509094045

Cited by 48 publications

(45 citation statements)

References 11 publications

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“…However, DNA sequencing showed only wildtype TP53 sequences in all six E7-HUCs, including the two cell lines with 20q13.2 ampli®cation and genomic instability, disproving this hypothesis. It has been proposed that p53 abnormalities play a role in generating genomic instability in primary human breast cancer (EyfjoÈ rd et al, 1995). However, it is clear from these and other studies that alternate pathways exist for chromosome instability and gene ampli®cation (Livingstone et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

et al. 1997

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Breast, bladder, colon, and ovarian carcinomas show frequent low level 20q gain and less frequently high level 20q13.2 ampli®cation, but the signi®cance of these 20q ampli®cations in transformation has not been de®ned. Using karyotypic and comparative genomic hybridization (CGH) analyses, chromosome losses and gains were analysed in six newly immortalized human uroepithelial cell (HUC) lines transformed by Human Papillomavirus 16 (HPV16) E7. Results showed clonal chromosomes with 20q11-4qter gain in all six lines. CGH revealed a peak of 20q13.2 ampli®cation in two cell lines. FISH with whole chromosome 20 paint showed expanded chromosome regions (ECRs) and double minute chromosomes (DMs) that contained chromosome 20 material in cell lines with 20q13.2 ampli®cation. FISH with probes from the center of the 20q13.2 human breast cancer amplicon showed as many as 24 signals in cells with 20q13.2 ampli®cation. The acquisition of genome instability in these E7-HUCs did not correlate with TP53 mutation, as all E7-HUCs contained only wildtype TP53. These results suggest that low level 20q gain is associated with overcoming cellular senescence in E7 transformed cells (P-value=2610 77 ), but does not confer genome instability, while high level 20q13.2 ampli®cation is associated with chromosome instability. Loss of 10p (P-value=3610 75 ) was also important in immortalization of E7-transformed HUCs. Thus, these results have profound implications for interpreting the signi®cance of high versus low level 20q gains in human cancers.

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Section: Discussionmentioning

confidence: 99%

20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

et al. 1997

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“…Genetic instability in breast cancer has been associated with mutations of the p53 tumor suppressor gene, (Eyfjord et al, 1995a;1995b) although some studies have not found this association (Deng et al, 1994). To determine if discordant LOH might reflect the presence of a p53 mutation, exons 5-8 of the p53 gene were sequenced in the normal tissue and tumor components of 11 cases with discordant LOH for which sufficient material was available.…”

Section: Assessment Of Cases For Microsatellite Instability Phenotypementioning

confidence: 99%

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Lichy

Dalbègue

Zavar

et al. 2000

Laboratory Investigation

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SUMMARY:Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones. (Lab Invest 2000, 80:291-301).E lucidation of the sequence of genetic events responsible for progression of breast cancer from in situ to infiltrating and metastatic carcinoma is an important goal of efforts to understand the biological basis of this common malignancy. Progression is believed to occur through the accumulation of genetic changes via a process of clonal evolution and clonal selection (Brenner and Aldaz, 1997;Nowell, 1976). Surgically resected breast carcinoma specimens provide a unique resource for analyzing the genetic changes that occur during progression, because specimens typically contain foci of tumor in various stages of progression, including in situ carcinoma, invasive tumor, and lymph node metastases. Morphologically normal epithelial constituents of the breast are usually represented in such specimens, and foci of benign proliferative epithelial lesions may also be present.Detailed studies of colon cancer have shown that adenomatous epithelium adjacent to carcinoma typically has some but not all of the genetic lesions present in the fully developed malignancy, consistent with direct progression from adenoma to carcinoma (Boland et al, 1995;Fearon and Vogelstein, 1990;Vogelstein et al, 1988). By analogy, it might be expected that a similar analysis of breast tumors in different stages of progression would likewise show the accumulation of genetic changes with progression. However, genetic analysis of breast cancer specimens has suggested that the individual foci of tumor identifiable by microscopic examination may not show the precursor-product relationship often observed in colon cancer. Cytogenetic studies in particular have revealed sufficient genetic...

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“…In a DNA repair pathway, recombinational processes may act to maintain genetic stability, but if deregulated or increased, genomic instability and malignant transformation can result. Importantly, increased HR could be a mechanism involved in loss of heterozygosity which is frequently observed in tumor development and progression (Cavenee et al, 1983;Koufos et al, 1984;EyfjoÈ rd et al, 1995). Thus, suppression of spontaneous HR is a means by which p53 can maintain genome stability.…”

Section: Introductionmentioning

confidence: 99%

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

et al. 2000

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The tumor suppressor p53 is considered as the guardian of the genome which is activated following genotoxic stress. In many cell types, p53 mediates G1 cell cycle arrest as the predominant cellular response. Inactivation of wild-type p53 leads to loss of G1/S checkpoint control and to genomic instability, including increased spontaneous homologous recombination (HR). To determine whether regulation of the G1/S checkpoint is required for suppression of HR, we assessed recombination events using a plasmid substrate that stably integrated into the genome of p53-null mouse ®broblasts. Exogenous expression of a temperature-sensitive p53 protein (Ala135 to Val), which had lost trans-activation function and could not regulate G1/S transition when in mutant conformation, reduced HR rates to the same extent as wild-type p53. Furthermore, a p53 construct with an alternatively-spliced carboxy terminus also retained this ability in the absence of both activities, G1/S control and non-sequence speci®c DNA binding as mediated by the carboxy terminus. Our data dissociate regulation of HR by p53 from its role as a cell cycle checkpoint protein.The results support a model which extends p53's role as a guardian of the genome to include transactivationindependent regulatory functions in DNA repair, replication and recombination. Oncogene (2000) 19, 632 ± 639.

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TP53 Abnormalities and Genetic Instability in Breast Cancer

Cited by 48 publications

References 11 publications

20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

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