KRAS mutation is a well-known marker for poor response to targeted treatment and patient prognosis in microsatellite stable (MSS) colorectal cancer (CRC). However, variation in clinical outcomes among patients wild-type for KRAS underlines that this is not a homogeneous population. Here, we evaluated the prognostic impact of KRAS alternative splicing in relation to mutation status in a single-hospital series of primary MSS CRCs (N = 258). Using splicing-sensitive microarrays and RNA sequencing, the relative expression of KRAS-4A versus KRAS-4B transcript variants was confirmed to be down-regulated in CRC compared to normal colonic mucosa (N = 41; p ≤ 0.001). This was independent of mutation status, however, gene set enrichment analysis revealed that the effect of splicing on KRAS signaling was specific to the KRAS wild-type subgroup, in which low relative KRAS-4A expression was associated with a higher level of KRAS signaling (p = 0.005). In concordance, the prognostic value of KRAS splicing was also dependent on mutation status, and for patients with Stage I-III KRAS wild-type MSS CRC, low relative KRAS-4A expression was associated with inferior overall survival (HR: 2.36, 95% CI: 1.07-5.18, p = 0.033), a result not found in mutant cases (p = 0.026). The prognostic association in the wild-type subgroup was independent of clinicopathological factors, including cancer stage in multivariable analysis (HR: 2.68, 95% CI: 1.18-6.09, p = 0.018). This suggests that KRAS has prognostic value beyond mutation status in MSS CRC, and highlights the importance of molecular heterogeneity in the clinically relevant KRAS wild-type subgroup.

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To my supervisors Rolf Skotheim and Bjarne Johannessen, your unwavering patience and bottomless knowledge have, time and again, proved invaluable to the realization of this thesis. To Torbjørn Rognes for being my internal supervisor at the Department for Informatics, University of Oslo. To my brilliant colleagues, past and present, in the Genome Biology group for your continued support, for the insightful discussions, and for the quizzes and mashed rutabagas at the Christmas parties. To Kristina for your solitary reign over the Social Committee, and for the editorial prowess displayed during the preparation of this thesis. To the wonderful people at the Department of Molecular Oncology for providing the professional environment in which I have grown, and for the friendships made along the way. To my co-authors Ina Eilertsen, Anita Sveen, and Ragnhild Lothe, and to our clinical collaborators Karol and Ulrika Axcrona for your valuable scientific contributions. To my friends for your compassion and understanding, and for listening to my sometimes-warranted and sometimes-maybe-not-so-warranted rants about academia, cancer research, and supercomputers. To my mother, my father, and my brothers, for cheering me on when my spirits were at their most diminished.Finally, to my beloved dog and lille gris Ferdinand, for being an inextinguishable flame of encouragement.