On October 15th 2021, Kristina Totland Carm successfully defended her thesis “Genomic aberrations and molecular subtypes in multifocal prostate cancer” for the PhD degree at the Medical Faculty, University of Oslo. She also gave a trial lecture on the given topic: “Multiparametric MRI-guided biopsies in prostate cancer diagnostics – challenges on the road towards radiogenomics”.
The adjudication committee included first opponent, Professor Ian Mills, University of Oxford, UK; second opponent, Professor Karl-Henning Kalland, University of Bergen, and chair of the evaluation committee was Associate Professor Stig Müller, University of Oslo. Chair of the defence was Associate Professor June Helen Myklebust, University of Oslo.
Principal Supervisor was Rolf I. Skotheim, and co-supervisors were Marthe Løvf, Andreas Hoff and Ragnhild A. Lothe.
The thesis included the following scientific papers:
I. Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer. Kristina T. Carm, Andreas M. Hoff, Anne Cathrine Bakken, Ulrika Axcrona, Karol Axcrona, Ragnhild A. Lothe, Rolf I. Skotheim, and Marthe Løvf. Scientific Reports 2019, 9: 13579
II. High expression of SCHLAP1 in primary prostate cancer is an independent predictor of biochemical recurrence, despite high degree of heterogeneity. Susanne G. Kidd*, Kristina T. Carm*, Mari Bogaard, Linn Guro Olsen, Anne Cathrine Bakken, Marthe Løvf, Ragnhild A. Lothe, Karol Axcrona, Ulrika Axcrona, and Rolf I. Skotheim. *Equal contribution Neoplasia 2021, 23(6): 634-641
III. Somatic mutations reveal complex metastatic seeding from multifocal primary prostate cancer. Kristina T. Carm, Bjarne Johannessen, Anne Cathrine Bakken, Mari Bogaard, Andreas M. Hoff, Ulrika Axcrona, Karol Axcrona, Ragnhild A. Lothe and Rolf I. Skotheim. Manuscript
Associated paper: Multifocal primary prostate cancer exhibits high degree of genomic heterogeneity. Marthe Løvf, Sen Zhao, Ulrika Axcrona, Bjarne Johannessen, Anne Cathrine Bakken, Kristina T. Carm, Andreas M. Hoff, Ola Myklebost, Leonardo A. Meza-Zepeda, A. Kathrine Lie, Karol Axcrona, Ragnhild A. Lothe and Rolf I. Skotheim. European Urology 2019, 75(3), 498-505
Summary of Kristina’s thesis:
Each year, 1.4 million men are diagnosed with prostate cancer globally, and many die from their disease. There is a pressing need for precise and robust biomarkers to separate the aggressive cancers from the more indolent ones. The multifocal and heterogeneous nature of the disease increases the level of complexity, greatly hindering the implementation of robust and informative prognostic tests. In this doctoral thesis, Kristina T. Carm and colleagues evaluated the usefulness of seven proposed molecular subtypes with different molecular analyses on a unique prostate cancer biobank, with multiple samples from spatially separated tumor foci. They found that the pronounced heterogeneity across and within tumors substantially decreased the fraction of successfully classified patients, thus weakening the potential clinical value of the subtypes.
Further, the researchers showed how high expression of a promising biomarker, the long non-coding RNA SCHLAP1, in any tumor sample from one patient was a predictor of poor prognosis. However, the level of heterogeneity was high; underscoring how multiple samples are instrumental in the search for robust biomarkers in prostate cancer prognostics and diagnostics.
Prediction of the aggressiveness of a patient’s cancer is highly sought after. Using a custom made targeted sequencing panel, Carm et al. tested for somatic mutations and explored the relationship between samples representing metastatic disease, as well as multiple primary tumor foci from radical prostatectomy specimens. Even though some mutations were shared between primary tissue and metastatic samples, the study revealed a highly complex molecular picture of the relationship between primary tumor foci and subsequent metastatic disease. Jointly, this thesis has elucidated prostate cancer as a multifaceted disease, and shown how development of diagnostic tools must take multifocality and heterogeneity into account.