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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Judith V. M. G. Bovee, Leiden University Medical Center, The Netherlands
- Second opponent: Group leader Marieke Kuijjer, University of Oslo
- Third member and chair of the evaluation committee: Professor Øyvind Bruland, University of Oslo
Chair of the Defence
Professor II Jørgen Wesche, University of Oslo
Principal Supervisor
Professor II Ragnhild Adelheid Lothe, University of Oslo
Summary
This thesis describes molecular tools for risk stratification and potential novel treatment options for patients with malignant peripheral nerve sheath tumor (MPNST).
MPNST is a rare soft tissue sarcoma that arises in the glial cells of the peripheral nerve system. This thesis is part of a European multicenter study, analyzing one of the largest collections of this tumor type in the world. Today, MPNST patients have few treatment options beyond surgery due to a lack of knowledge on the molecular drivers of the disease.
Half of the tumors arise in patients with the common hereditary syndrome neurofibromatosis type 1 (NF1). In a meta-analysis, MPNST patients with or without NF1 were found to have comparable poor prognosis, with less than 50% five-year survival. Furthermore, NF1-associated and sporadic tumors had similar set of DNA aberrations, and gain of DNA material was strongly associated with poor prognosis. Gain of three genes on chromosome arm 17q (BIRC5, TK1, and TOP2A) were validated on the protein level in tumor tissue sections, and identified an “easy-to-perform” test for patient risk stratification.
Unsupervised gene expression-based classification defined two novel subtypes independent of NF1-status. One of the subtypes had strong downregulation of immune-related processes (termed “immune deficient”), and these MPNSTs had a higher burden of DNA aberrations and were associated with an inferior prognosis as compared to tumors with sustained immune activity (termed “immune active”). We suggested that immune therapy with immune checkpoint inhibitors might be effective against immune active MPNSTs, while targeting specific oncogenes might be effective against immune deficient tumors.
Overall, development of MPNSTs seems to be driven mainly by loss and gain of DNA material. TP53, one of the few genes with recurrent point mutation, was mutated in 8.2% of MPNSTs; however, 60% of the tumors shared a common “TP53-mutated phenotype” associated with inferior prognosis.
Additional information
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