As part of a long-term collaboration between the Section for Cancer Cytogenetics at the Institute for Medical Informatics and Section for Molecular Oncology at the Institute for Cancer Research, a joint PhD project has been carried out to study RNA changes in ovarian cancer.
The PhD work concluded on March 17th, when Cand. med. Marianne Lislerud Smebye successfully defended her thesis "Transcriptomic consequences of chromosome 19 rearrangements in ovarian carcinomas" for the PhD degree. The same day, she held an excellent trial lecture over the given topic "Chromosomal abnormalities and copy number rearrangements as clinical targets in cancer". The PhD work was jointly surpervised between Francesca Micci (main supervisor), Sverre Heim and Rolf Skotheim.
Each year about 450 Norwegian women are diagnosed with ovarian cancer. The five-year survival rate is only 44%. To develop novel targeted therapies and clinically relevant biomarkers, it is essential for us to understand the mechanisms of cancer development. Ovarian carcinomas, the most common type of ovarian cancer, are characterized by a high degree of DNA rearrangements. Aberrations of chromosome 19 are particularly common and it is likely that these are pathogenetically important. The main aim of this PhD project was to gain insight into the RNA-level consequences of these genomic rearrangements. The starting point for the present work was a cohort of ovarian carcinomas carrying structural alterations of chromosome 19. These were analyzed using exon-level microarrays, RNA sequencing, Sanger sequencing, and RT-PCR. Our studies showed that the genomic amplification was particularly associated with higher expression of a gene family called zinc finger genes. These genes function as transcription factors, but it is largely unknown which genes they regulate.
At the time of diagnosis, ovarian cancer often affects both ovaries. By comparing gene expression profiles in the left and right ovaries of four patients, we found that bilateral ovarian carcinomas differ in the expression of metastasis-related genes, such as SERPINE1. The identified genes could be involved in the metastatic spreading from one side to the other in the examined bilateral cancer cases. We also did a separate analysis of the chromosome 19 gene set, and this highlighted differences in expression of the zinc finger gene ZFP36. Structural rearrangements can lead to formation of so-called fusion genes by translocation of genomic material between chromosomes. A fusion gene is a hybrid gene consisting of parts of two previously independent genes. Identification of such genes is important since they have great potential as cancer-specific tumor markers or as drug targets. In a sample carrying a genomic translocation between chromosomes 11 and 19, we identified DPP9-PPP6R3, a corresponding fusion transcript. Several other potential fusion gene partners were also identified.
Section for Molecular Oncology
Section for Cancer Cytogenetics
Dissertation announcement at the University of Oslo