University of Iceland
Activity: Examination
Breast carcinoma, the most common cancer in women in the Western world, frequently shows complex karyotypes with multiple chromosomal changes. In this thesis the focus is on genomic alterations that may play a role in increasing chromosomal instability, such as amplification of oncogenes and dysfunctional telomeres. Of special interest are breast tumour samples with mutations in the BRCA2 and TP53 genes, which are known to induce chromosomal instability. The genomic alterations most often found in selected breast tumour samples with chromosomal instability were gains on chromosomes 8q and 20q. Candidate oncogenes on these chromosome arms known to be associated with chromosomal instability are MYC on 8q24 and AURKA on 20q13. Oncogene MYC amplification analysis was performed on 27 paraffin-embedded breast tumour samples by FISH. Amplification of MYC was detected in 59% of tumours and found to be significantly associated with TNM stages I and II (p = 0.018), high genomic index (p = 0.033), and high S-phase fraction (p = 0.020). Potential association of AURKA oncogene amplification and BRCA2 mutation was examined in breast tumours from BRCA2 mutation carriers (n = 20) and non-carriers (n = 41). AURKA amplification studied by FISH was found in 70% of BRCA2-mutated breast tumours and was highly associated with BRCA2 mutation carriers (p < 0.001). Extensive AURKA amplification was also detected on metaphase chromosomes in three breast epithelial cell lines with a BRCA2 mutation. In addition, significant association was found between AURKA amplification and TP53 mutations in non-BRCA2 mutation carrier tumours (p = 0.007). These results suggest that breast tumours with mutations in BRCA2 or TP53 could be promising candidates for AURKA targeted treatment. Possible involvement of telomeres in chromosomal instability of BRCA2-mutated breast tumours and cell lines was examined. Breast tumours and cell lines from BRCA2 mutation carriers showed significantly higher frequency of chromosome end fusions than tumours from non-carriers even though telomere DNA content was normal. Chromosome end fusions were shown to be both between telomeres and between telomeres and double strand breaks, which implies telomere end capping defects. Telomere signals were frequently lost and telomere sister chromatid exchanges were frequent in BRCA2-mutated cell lines, characteristic of cells using alternative lengthening of telomeres. These results indicate that BRCA2 may have an important role in telomere stabilization.