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Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival
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, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
1999 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 80, no 5/6, 843-849 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies have demonstrated that the pathological features of breast cancer are more aggressive in younger women than in their older counterparts, and that young age may be an independent marker for adverse prognosis. These findings have raised the question whether these differences are also present at the molecular level. In order to characterize the genetic alterations associated with early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were examined for loss of heterozygosity (LOH) at nine different loci on chromosomes 11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in 43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and D11S387 markers, which expressed LOH in 53% and 48% of the informative cases, whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency of 24%. A statistically significant correlation was found between LOH at the D11S387 marker and poor survival (P = 0.028). No such correlation was found for the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387. We conclude that one or more as yet unidentified genes, situated in chromosome bands 11q24.1–q25, could be involved in the initiation and/or progression of breast cancer in younger women.

Place, publisher, year, edition, pages
1999. Vol. 80, no 5/6, 843-849 p.
Keyword [en]
early onset breast cancer, young age, poor prognosis, LOH analysis, 11q24.1–q25
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24992DOI: 10.1038/sj.bjc.6690430Local ID: 9412OAI: oai:DiVA.org:liu-24992DiVA: diva2:245316
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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Dufmats, MonikaWingren, Sten

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