Digital public defence: Tuva Høst Brunsell
MD Tuva Høst Brunsell at Institute of Clinical Medicine will be defending the thesis Heterogeneity of prognostic biomarkers in colorectal liver metastases for the degree of PhD (Philosophiae Doctor).
The public defence will be held as a video conference over Zoom.
The digital defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Digital trial lecture - time and place
- First opponent: Professor Karen-Lise Garm Spindler, Aarhus University, Denmark
- Second opponent: Professor Helgi Birgisson, Uppsala University, Sweden
- Third member and chair of the evaluation committee: Professor Frode Jahnsen, Institute of Clinical Medicine, University of Oslo
Chair of defence
Professor Ludvig André Munthe, Institute of Clinical Medicine, University of Oslo
Professor II Arild Nesbakken, Institute of Clinical Medicine, University of Oslo
Colorectal cancer (CRC) is the second most common cause of cancer and cancer-related death in Norway. Most deaths are due to disseminated disease, with the liver being the most common site of distant spread (metastases). A potentially curative resection of liver metastases is performed in a subgroup of the patients, but 70% experience recurrence and less than 50% survive more than five years. While tumor heterogeneity could be an explanation for treatment failure, it has been almost unexplored among multiple metastases in CRC. The aim of this thesis was to explore intra-patient inter-tumor heterogeneity of driver gene mutations, DNA copy number aberrations (CNAs) and response to neoadjuvant treatment in resected CRC liver metastases. In addition, the prognostic impact of mutations and CNAs was explored.
We performed mutation analyses of multiple liver metastases from each patient with Sanger sequencing and high sensitivity methods, namely targeted next-generation sequencing and droplet digital PCR. We demonstrated near-perfect intra-patient concordance of mutations in the driver genes KRAS, NRAS, BRAF, PIK3CA and TP53, provided that high sensitivity methods were used. In contrast, DNA copy number analyses of the same tumors revealed highly variable intra-patient levels of CNAs.
RAS mutations alone had a significant, but modest impact on survival after surgery for liver metastases, but combined RAS and TP53 mutations had a major impact on survival. Patients with RAS/TP53 co-mutations and high CNA heterogeneity had particularly poor outcome.
A detailed radiological evaluation of response to neoadjuvant treatment was performed in patients with multiple liver metastases. Heterogeneity of response, defined as both response and progression of liver metastases with a diameter change of ≥3-5 mm on CT/MRI, was identified in about 10% of patients, depending on the cut-off value used. This patient group had poor survival after resection of the liver metastases.
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