Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Associate Professor Jesper Bertram Bramsen, Aarhus University Hospital, Denmark
- Second opponent: Research Group Leader Anthony Mathelier, Centre for Molecular Medicine Norway (NCMM)
- Third member and chair of the evaluation committee: Professor Mette Kalager, University of Oslo
Chair of the Defence
Professor Pål Dag Line, University of Oslo
Principal Supervisor
Professor II Ragnhild A. Lothe, University of Oslo
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Cancer staging remains the key determinant of patient prognosis and treatment decisions, but clinical outcome varies greatly, and this can partly be explained by molecular tumor heterogeneity. Gene expression-based subtyping can identify biologically distinct and clinically relevant subgroups of CRC. However, there are currently no standardized assays for transcriptomic cancer classification.
In this work, we compared gene expression profiling by exon-resolution microarrays and RNA sequencing in a series of primary CRCs to address the potential effects of technology platform on transcriptomic subtyping. We found that systematic technical biases related to gene lengths and expression levels had an impact on subtype distributions according to the gene expression-based consensus molecular subtypes (CMS) and CRC intrinsic subtypes (CRIS), highlighting the need for assay standardization prior to clinical translation of known CRC subtyping frameworks.
Despite benefit from targeted therapy and good prognostic associations for wild-type KRAS in microsatellite stable CRC, variation in clinical outcome indicates that this is not a homogeneous subgroup. By splicing-sensitive expression analysis of primary tumors, we found that aberrant splicing regulation of the KRAS-4A versus KRAS-4B transcript variant was associated with poor survival specifically in the KRAS wild-type subset, suggesting that this gene has prognostic value beyond mutation status.
Finally, we extended the splicing-sensitive analysis to a transcriptome-wide scale and identified pronounced cancer-specific splicing heterogeneity both within and across primary tumors. We defined the "tumor splicing burden" as the total number of aberrantly spliced events per tumor sample and showed that this molecular feature was associated with patient survival, highlighting that aberrant splicing contributes to tumor heterogeneity in CRC.
Additional information
Contact the research support staff.