Doctoral dissertation

High grade ovarian cancer and early pathogenesis

Ovarian cancer is the deadliest of gynecological cancers. In Finland, each year approximately 450 women are diagnosed and 300 women die of the disease. Research is necessary to provide means to improve the treatment and prognosis of this deadly disease. In this dissertation, early pathogenesis and response to therapy were investigated.

Early diagnosis of ovarian cancer is difficult to make and treatment of progressed disease is challenging. The gold standard of treatment consists of surgery combined with chemotherapy. The 5-year prognosis for all stages is approximately 45%. New targeted therapies are continuously investigated in the effort to improve the prognosis. PARP-inhibitors are a targeted treatment that is also available in Finland, currently for recurrent disease. Active research is paramount in order to find new targeted treatments and thus better understand which patient groups benefit.

In the first publication, the early pathogenesis of epithelial ovarian cancer was investigated by comparing the genome-wide gene expression levels in BRCA1/2 -mutation-positive risk-reducing salpingo-oophorectomy samples (RRSO) to those in healthy controls. The study revealed differentially expressed genes by microarray analysis, from which selected genes were validated by quantitative real time polymerase chain reaction, demonstrating comparable expression patterns between BRCA1/2-mutation-positive RRSO and high-grade serous ovarian cancer samples.

In addition, PARP expression in ovarian cancer samples was investigated. A PARP pharmacodynamic assay revealed an association between high PARP activity and platinum sensitivity and longer progression-free survival, which is a novel finding. Also, PARP pharmacodynamic assay may reflect more biologically significant PARP relative to PARP immunohistochemistry measurement.

Third, exploring chemoresistance in ovarian cancer was undertaken, yielding a novel result showing the association of differential expression of ROR2 and GREB1 with treatment response. In detail, the Wnt5a/ROR2 pathway was found to be potentially actionable in the possible modulation of chemoresistance in epithelial ovarian cancer. A combination of ROR antagonists and chemotherapeutic agents may be an investigation-worthy option in the future, as silencing ROR1 and ROR2 restores the chemosensitivity of carboplatin-resistant ovarian cancer cells.

In this dissertation, early pathogenesis of epithelial ovarian cancer and aspects of treatment sensitivity were investigated.

Kristina Veskimäe is from Estonia. She earned medical degree (M.D.) from Tartu University in 2005 and gynecology and obstetrics specialist degree from Tampere University in 2013. Kristina Veskimäe is a gynecology and obstetrics consultant in Tampere University Hospital.

The public examination of the doctoral dissertation of Kristina Veskimäe, M.D. in the field of gynecology and obstetrics titled High Grade Serous Ovarian Cancer Expression Profiling, Aspects of Early Pathogenesis and Potential Mechanisms of Chemoresistance will be held at the Faculty of Medicine and Health Technology of Tampere University on Friday, 13th of December, 2019 at 12 o’clock in the Arvo building Auditorium F114, Arvo Ylpön katu 34. The Opponent is Docent Heini Lassus from Helsinki University and the Custos is Professor Johanna Mäenpää from Tampere University.

The dissertation is available at: http://urn.fi/URN:ISBN:978-952-03-1345-6

Photograph: Pille Aro