Genetic aberrations and their clinical significance in breast and ovarian cancer
1Oulu University Hospital, Department of Clinical Genetics
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|Persistent link:|| http://urn.fi/urn:isbn:9514251946
|Publish Date:|| 1999-03-26
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 9 of the University Hospital of Oulu, on April 16th, 1999, at 12 noon.
Professor Olli-Pekka Kallioniemi
Professor Catharina Larsson
In tumourigenesis, genetic alterations accumulate in the genes responsible for cell growth, proliferation and DNA repair: proto-oncogenes, tumour suppressor and DNA repair genes. Inactivation of tumour suppressor gene function is commonly recognised as a deletion of one of the two alleles; LOH, loss of heterozygosity. In the present study, LOH of several chromosomal regions was studied in both breast and ovarian cancer.
LOH for chromosome region 11q was examined in a large breast cancer consortium cohort (N = 988) and in a Finnish ovarian cancer cohort (N = 78), and the clinical significance of these alterations was evaluated. In breast cancer, LOH of the studied markers at 11q23.1, harbouring approximately 2 Mb of DNA, was seen to be associated with shortened cancer-specific survival. Two candidate genes, ATM (the ataxia telangiectasia disorder gene) and DDX10 (a putative RNA helicase gene) map to this chromosomal region.
In ovarian cancer, LOH at 11q23.1–q24 was assigned mainly to two chromosomal regions, A and B, which are proximal and distal to 11q23.2–q23.3, respectively. Only the distal B region was seen to be associated with an aggressive disease course. Therefore, it appears that inactivation of the ATM or DDX10 genes is not crucial for determining the outcome of ovarian cancer. The CHK1 gene at 11q24, encoding a protein kinase required for DNA damage checkpoint function, is a putative target gene at the B region. On the basis of the present results, the main TSG in the studied region involved in the progression of breast cancer maps to 11q23.1 and the corresponding gene for ovarian cancer more distally to 11q23.3-q24.
In addition, LOH at 3p, 6q, 8p, 11p, 16q and 17p was examined and their role in the genetic evolution of ovarian cancer was evaluated. Of the studied chromosomal regions, LOH at 17p appeared to be an early event and LOH at 16q24.3, 11q23.3/q24 and 11p appear to occur later in the progression of ovarian cancer.
Acta Universitatis Ouluensis. D, Medica
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