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Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
Department of Pathology and Cytology, Kalmar County Hospital, Kalmar, Sweden.
Department of Oncology, Jubileum Institute, University Hospital, Lund, Sweden.
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2001 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 92, nr 2, s. 208-213Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Frequent allelic deletions at chromosome 11q24-q25 have been described in both early and late onset breast cancers, suggesting the existence of a gene locus implicated in the initiation and/or progression of the disease. In the present study we fine mapped this region further by loss of heterozygosity (LOH) analysis in a population of early onset breast cancer cases (n = 102, 22 to 36 years old). Loss of chromosomal material was assessed for possible association with patient survival as well as Nottingham histologic grade (NHG). Additionally, we investigated the involvement of the 11q24-q25 locus in a group of familial breast cancer cases with no detectable BRCA1 or BRCA2 gene alterations (n = 32, ages 28 to 40 years). Among the consecutive patients, extensive LOH was observed for all markers at 11q24-q25, with frequencies ranging from 42% to 54%. Deletion at the D11S4125 marker was found to be associated with reduced survival (p = 0.026), whereas the adjacent D11S387 marker correlated with higher histologic grade (p = 0.042). In the familial cases, the most telomeric markers showed substantially lower proportions of LOH, ranging from 10% to 21%. Comparison of the two patient groups demonstrated that this difference in LOH frequency was statistically significant for the D11S4098, D11S968, D11S387 and D11S4125 markers (p = 0.020, p = 0.029, p = 0.0070 and p = 0.0030, respectively). We conclude that 11q25 may harbor a gene implicated in early onset breast cancer. Our data suggest that the most probable position for this locus is defined by the markers D11S387 and D11S4125 and furthermore that it may play a less significant role in familial breast cancer cases not linked to either of the BRCA genes.

Ort, förlag, år, upplaga, sidor
2001. Vol. 92, nr 2, s. 208-213
Nyckelord [en]
11q, LOH, early onset, familial breast cancer, prognosis, young age
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-49326DOI: 10.1002/1097-0215(200102)9999:9999<::AID-IJC1169>3.0.CO;2-4OAI: oai:DiVA.org:liu-49326DiVA, id: diva2:270222
Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
Ingår i avhandling
1. Genetic Alterations in Early Onset Breast Cancer
Öppna denna publikation i ny flik eller fönster >>Genetic Alterations in Early Onset Breast Cancer
2001 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköpings universitet, 2001. s. 89
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 686
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-25647 (URN)10023 (Lokalt ID)91-7219-980-6 (ISBN)10023 (Arkivnummer)10023 (OAI)
Disputation
2001-09-26, Administrationsbyggnadens aula, Universitetssjukhuset, Linköping, 09:00 (Svenska)
Opponent
Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2012-09-10Bibliografiskt granskad

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