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Genetic Alterations in Early Onset Breast Cancer
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-25647Local ID: 10023ISBN: 91-7219-980-6 (print)OAI: oai:DiVA.org:liu-25647DiVA: diva2:246195
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
List of papers
1. p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation
Open this publication in new window or tab >>p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24932 (URN)10.1016/S0959-8049(99)00121-5 (DOI)9338 (Local ID)9338 (Archive number)9338 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival
Open this publication in new window or tab >>Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival
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.

Keyword
early onset breast cancer, young age, poor prognosis, LOH analysis, 11q24.1–q25
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24992 (URN)10.1038/sj.bjc.6690430 (DOI)9412 (Local ID)9412 (Archive number)9412 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
Open this publication in new window or tab >>Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
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2001 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 92, no 2, 208-213 p.Article in journal (Refereed) 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.

Keyword
11q, LOH, early onset, familial breast cancer, prognosis, young age
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-49326 (URN)10.1002/1097-0215(200102)9999:9999<::AID-IJC1169>3.0.CO;2-4 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved
4. Candidate tumour suppressor genes at 11q23-q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis
Open this publication in new window or tab >>Candidate tumour suppressor genes at 11q23-q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis
2001 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 53, 7753-7760 p.Article in journal (Refereed) Published
Abstract [en]

One of the most consistently deleted chromosomal regions in solid tumours is 11q23-q25, which consequently has been postulated to harbour one or more tumour suppressor loci. Despite large efforts to identify the responsible genes, the goal remains elusive, but as knowledge accumulates new candidates are emerging. The present study was undertaken in an attempt to assess the possible implication of four genes residing at 11q23-q24, in a population of early onset breast cancer (n=41). The coding sequence of PIG8, CHK1, LOH11CR2A and PPP2R1B were screened for mutations using the protein truncation test or single-strand conformational polymorphism, in combination with direct DNA sequencing. Varying proportions of alterations were detected, ranging from 6% in PPP2R1B to 39% in PIG8. Many of these changes were deletions, in some cases corresponding to complete exons, thus likely to represent splice variants, while others were presumed to arise from aberrant splicing, since they occurred at sites with resemblance to exon/intron borders. Considering only bona fide mutations, the highest alteration frequency (17%) was again found in PIG8. Most of these alterations were likely to have an adverse impact on the translated protein as they either altered the reading frame or affected phylogenetically conserved residues. Our data represent the first evidence of alterations in the PIG8 gene in human malignancies, a finding that substantiates its role as a potential tumour suppressor gene as suggested by its involvement in p53-induced apoptosis. 

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24841 (URN)10.1038/sj.onc.1204993 (DOI)9239 (Local ID)9239 (Archive number)9239 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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