Decoding Genetic Enigmas in Sarcoma

Sarcomas represent a broad and heterogenous group of rare tumors. For some subtypes, there are
pathognomonic genetic alterations available, while for others such alterations remain to be identified.
Especially in entities that harbor large numbers of complex genetic changes, much still remains to be
understood. One such entity is osteosarcoma, the most common primary bone tumor. Although primarily
affecting children and adolescents, this tumor typically presents a chaotic genome. In Papers I-III, we
present different genetic mutational mechanisms that distinguish osteosarcoma sub-entities with different
biology and tumor behavior. Namely, we present a recurrent mechanism involving the promoter region
of the TP53 tumor suppressor gene in a subset of conventional osteosarcomas. We demonstrate that
structural variants abrogate TP53 expression but also relocate its promoter region. By responding to
ongoing DNA damage, it in turn leads to upregulation of known or putative oncogenes erroneously
translocated into its vicinity. Additionally, we subdivide 12q-amplified osteosarcomas into four distinct
groups and show that recurrent promoter swapping events involving the FRS2 and PLEKHA5 regulatory
regions occur in many high-grade and dedifferentiated osteosarcomas with CDK4 and MDM2
amplification. Moreover, we found that osteosarcomas with relatively few chromosomal alterations or
adult onset are genetically heterogenous. Finally, in the last part of the thesis (Papers III-IV), we
introduced new bioinformatics tools: (i) NAFuse to detect gene fusions; (ii) the genomic complexity score
(GCS) to analyze the complexity genome-wide; and (iii) SarcDBase, a tool that integrates genomic and
transcriptomic data with existing information. Collectively, this thesis has advanced our understanding of
the role played by specific mutations in the development and progression of osteosarcoma and has
introduced new bioinformatics tools that facilitate the analysis and interpretation of highly complex
genetic information.