Prostate cancer

The Skotheim group is responsible for the ongoing research projects related to this disease in Department of Molecular Oncology. Lothe has contributed to the initiation and development of one of these projects as a co-director for CoE-Cancer Biomedicine, and has co-supervised four PhDs in prostate cancer research with Skotheim as main supervisor.

Long term collaboration (2000 onwards) with Prof Manuel R Teixeira is documented by 34 joint papers, and as external supervisor Lothe have hosted four PhD students from the Portuguese Institute of Oncology.

Colorectal cancer

We perform translational research on colorectal cancer in an interdisciplinary research program. The program is a collaborative network of biomedical researchers and clinicians from different disciplines and at different sites of the hospital. Our research group represents the core experimental lab and computational analysis unit.

Ovarian cancer: molecular landscape in context of heterogeneity

The research program is a multidisciplinary effort within Oslo University Hospital, and includes partners from the  Institute for Cancer Research, Department of Molecular Oncology and Department of Immunology (Kjetil Taskén lab), Department of Gynaecologic Oncology (Anne Dørum and Katharina Bischoff), and Department of Pathology (Ben Davidson). The subprojects of the Department of Molecular Oncology is run jointly by the Skotheim lab and Lothe lab with the following scientists involved: Bjarne Johannessen, Anita Sveen, Mie Jareid and Solveig Klokkerud.


Ovarian cancer (OC) is a global health challenge and is renowned as the most lethal among gynaecological cancers. Two-thirds of the OC patients have metastases already at diagnosis. Patients with localized disease have a five-year survival rate of 80-90%, but drastically lower at approximately 30% and 15% for those diagnosed with stage III and IV OC, respectively. Standard primary treatment of advanced OC has until recently been radical surgery with adjuvant or neoadjuvant platinum and paclitaxel chemotherapy. However, chemotherapy resistance and toxicity, often after repeated cycles with chemotherapy, is the main reason for treatment failure. Targeted therapy with patient benefit is first-line poly (ADP-ribose) polymerase (PARP) inhibitors. Aditionally, maintenance treatment with bevacizumab following a relapse of platinum-sensitive cancer prolongs the average progression-free survival. Epithelial OC is categorized into type I (~25%) and II (~75%). High grade serous OC is the most aggressive among type II cancers and almost all have mutations in the TP53 gene and about one in five in BRCA1/2.

Knowledge of the molecular biology of OC is important to improve treatment and prolong survival. The aim of our research is to understand the clonal evolution, including the molecular heterogeneity of disease progression and chemoresistance. We compare inter and intra-tumour heterogeneity, including the molecular characterisation of multiple samples from individual and successive tumours from each patient taken during disease progression. The studies include both patients with known genetic predisposition and sporadic OC. A long-term goal is to develop biomarkers for early detection and to suggest novel intervention strategies.

Projects

  1. Multi-level molecular profiling of OC in a heterogeneity context
    • Spatiotemporal heterogeneity in high grade serous ovarian cancer (HGSOV)
  2. Development of prognostic and predictive biomarkers

Selected publications

Sveen A, Johannessen B, Klokkerud SMK, Kraggerud SM, Meza-Zepeda L, Bjørnslett M, Bischof K, Myklebost O, Tasken K, Skotheim RI, Dørum A, Davidson B, and Lothe RA (2024). Evolutionary mode and timing of dissemination of high-grade serous carcinomas. JCI Insight 9(3): e170423

Smebye ML, Agostini A, Johannessen B, Thorsen J, Davidson B, Tropé CG, Heim S, Skotheim RI, and Micci F (2017). Involvement of DPP9 in gene fusions in serous ovarian carcinoma. BMC Cancer 17(1): 642

Smebye ML, Sveen A, Haugom L, Davidson B, Tropé CG, Lothe RA, Heim S, Skotheim RI, and Micci F (2014). Chromosome 19 rearrangements in ovarian carcinomas: Zinc finger genes are particularly targeted. Genes Chromosomes Cancer 53(7): 558-67

Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, Rajpert-De Meyts E, and Lothe RA (2013). Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: Implications for pathogenesis. Endocrine Reviews 34(3): 339-76

Micci F, Skotheim RI, Haugom L, Weimer J, Eibak AM, Abeler VM, Trope CG, Arnold N, Lothe RA, and Heim S (2010). Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes. Genes Chromosomes Cancer 49(11): 1046-53

Micci F, Weimer J, Haugom L, Skotheim RI, Grunewald R, Abeler VM, Silins I, Lothe RA, Trope CG, Arnold N, and Heim S (2009). Reverse painting of microdissected chromosome 19 markers in ovarian carcinoma identifies a complex rearrangement map. Genes Chromosomes Cancer 48(2): 184-93

Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E, and Lothe RA (2007). Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol. Cancer 6: 12

Kraggerud SM, Szymanska J, Abeler VM, Kaern J, Eknaes M, Heim S, Teixeira MR, Tropé CG, Peltomäki P, and Lothe RA (2000). DNA copy number changes in malignant ovarian germ cell tumors. Cancer Res. 60(11): 3025-30

Malignant peripheral nerve sheath tumour (MPNST)

The incidence of malignant peripheral nerve sheath tumour (MPNST) is low in the general population, but individuals with the hereditary disease neurofibromatosis type 1 (NF1) are at greatly increased risk to develop this cancer. About two-thirds of all MPNSTs arise in neurofibromas, often of the plexiform type and in the setting of NF1. Early detection and the differential diagnosis of MPNST remain medical challenges. MPNSTs are highly aggressive and the patients have a poor prognosis.

Development of targeted therapies based on recent advances in molecular biology have been raised as key strategy in the “International consensus statement on MPNST in Neurofibromatosis 1”.

The NF1 tumor suppressor gene maps to chromosome band 17q11.2, and encodes the neurofibromin protein which function as a suppressor of RAS mediated signaling. Neurofibromin is expressed in the Schwann cells from which the MPNSTs are believed to originate. Individuals with NF1 carry a germline mutation in this gene. Several studies have shown loss of chromosome arm 17q sequences including the NF1 locus. Thus, a complete inactivation of NF1 is assumed to contribute to development of MPNSTs. Potential therapies include inactivation of RAS by preventing post-translational modifications like farnesylation or to block downstream targets of the RAS mitogenic signaling pathway. Somatic mutations in NF1 are also reported in benign neurofibromas, showing that additional genetic events beside inactivation of NF1 are necessary for malignant transformation.

In contrast to several soft tissue sarcomas no pathognomonic structural aberration has been found in MPNST that rather display complex karyotypes. However, recurrent chromosomal alterations have been identified in MPNSTs, including loss of 9p21, shown to reflect downregulated expression of CDKN2A (p16). Further, we have recently shown that frequent gain of 17q (distal to the map position of NF1) partly explain the upregulation of TOP2A, which is typically present in MPNST from patients with poor disease outcome (Skotheim et al., 2003). It has also been suggested that loss of TP53 function contribute to MPNST progression, but biallelic inactivation is rare in these tumours.

Testicular germ cell tumour

This project is currently run jointly between the Skotheim lab and Lothe lab at the Department of Molecular Oncology.

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