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p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
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1999 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 35, no 8, 1202-1207 p.Article in journal (Refereed) Published
Abstract [en]

The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age <37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P=0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.

Place, publisher, year, edition, pages
1999. Vol. 35, no 8, 1202-1207 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24932DOI: 10.1016/S0959-8049(99)00121-5Local ID: 9338OAI: oai:DiVA.org:liu-24932DiVA: diva2:245256
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Genetic Alterations in Early Onset Breast Cancer
Open this publication in new window or tab >>Genetic Alterations in Early Onset Breast Cancer
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is in essence a genetic disease, brought about by an accumulation of alterations in genes that encode proteins responsible for the control of cell growth, cell death and the maintenance of genomic integrity. Recent years have seen the unravelling of numerous genes that are targeted in carcinogenesis. Although several genes implicated in breast cancer have been identified, a substantial proportion of breast cancer cases is not linked to any definite gene, implying that more gene targets remain to be discovered. Based on clinicopathological differences observed between early and late onset breast cancers, it has been proposed that they may be biologically different with separate genetic origins and/or development. The work included in this thesis was initiated with the intent to identify some of the genetic aberrations that characterise early onset breast cancer.

The p53 protein is central in cell cycle control and alterations in its gene sequence are among the most commonly observed genetic events in human malignancies. The present study investigated the occurrence of p53 aberrations both at the protein and the gene level. Mutations were found in 17% of the cases, whereas loss of heterozygosity (LOH) and protein accumulation were observed in 42% and 46% of cases,respectively. Mutations situated in either of the L2 and L3 loops of the zinc-binding domain were found to confer a more adverse prognosis, when compared with mutations outside this region or wild-type gene (P=0.0007).

LOH was further assessed for loci mapping to commonly altered chromosome regions on llq, 13q and 17p,q. High proportion of LOH was found for the BRCA1 locus and for the 11q24-q25 region where no tumour-associated gene has previously been identified. Moreover, patients with losses of this locus were observed to have a poorer prognosis (p=0.02S). In order to pinpoint the location of this putative tumour-associated gene locus, five additional microsatellite markers were scored for LOH. Association with poor prognosis, as well as with higher Nottingham Histologic Grade, narrowed the region to achromosome segment spanning approximately 500 kb. The importance of this chromosomal region was also evaluated in a group of familial breast cancers without linkage to either of the breast cancer susceptibility genes BRCA1 and BRCA2. Data demonstrated significantly lower occurrence of LOH for the majority of the markers, suggesting a less important role for the 11q24-q25 region in this subset of patients.

Based on putative or known function, candidate genes located in proximity of the region identified above were selected for mutation screening. Of the investigated candidate genes, by virtue of the relatively high occurrence of alterations in its mRNA and its proposed function as mediator of apoptosis, PIG8 stood out as the most promising candidate.

In addition to confirming the involvement of gene loci previously shown to be implicated in breast cancer, a region on chromosome llq was identified that may harbour a gene of importance for the disease course of early onset cases. The most promising candidate gene appears to be PIG8, which has been proposed to mediate p53-induced apoptosis.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 89 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 686
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25647 (URN)10023 (Local ID)91-7219-980-6 (ISBN)10023 (Archive number)10023 (OAI)
Public defence
2001-09-26, Administrationsbyggnadens aula, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-10Bibliographically approved

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Bergman Jungeström, MalinSöderkvist, PeterWingren, Sten

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