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- Difilippo, Valeria
(författare)
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Decoding Genetic Enigmas in Sarcoma
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sarcomas represent a broad and heterogenous group of rare tumors. For some subtypes, there arepathognomonic 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 beunderstood. One such entity is osteosarcoma, the most common primary bone tumor. Although primarilyaffecting children and adolescents, this tumor typically presents a chaotic genome. In Papers I-III, wepresent different genetic mutational mechanisms that distinguish osteosarcoma sub-entities with differentbiology and tumor behavior. Namely, we present a recurrent mechanism involving the promoter regionof the TP53 tumor suppressor gene in a subset of conventional osteosarcomas. We demonstrate thatstructural variants abrogate TP53 expression but also relocate its promoter region. By responding toongoing DNA damage, it in turn leads to upregulation of known or putative oncogenes erroneouslytranslocated into its vicinity. Additionally, we subdivide 12q-amplified osteosarcomas into four distinctgroups and show that recurrent promoter swapping events involving the FRS2 and PLEKHA5 regulatoryregions occur in many high-grade and dedifferentiated osteosarcomas with CDK4 and MDM2amplification. Moreover, we found that osteosarcomas with relatively few chromosomal alterations oradult onset are genetically heterogenous. Finally, in the last part of the thesis (Papers III-IV), weintroduced 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 andtranscriptomic data with existing information. Collectively, this thesis has advanced our understanding ofthe role played by specific mutations in the development and progression of osteosarcoma and hasintroduced new bioinformatics tools that facilitate the analysis and interpretation of highly complexgenetic information.
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| 2. |
- Difilippo, Valeria, et al.
(författare)
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Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous
- 2024
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Ingår i: Laboratory investigation; a journal of technical methods and pathology. - 1530-0307. ; 104:1
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Tidskriftsartikel (refereegranskat)abstract
- Osteosarcoma is the most common primary bone malignancy, often detected in children and adolescents and commonly associated with TP53 alterations along with a high number of chromosomal rearrangements. However, osteosarcoma can affect patients of any age, and some tumors display less genetic complexity. Besides TP53 variants, data on key driving mutations are lacking for many osteosarcomas, particularly those affecting adults. To detect osteosarcoma-specific alterations, we screened transcriptomic and genomic sequencing and copy number data from 150 bone tumors originally diagnosed as osteosarcomas. To increase the precision in gene fusion detection, we developed a bioinformatic tool denoted as NAFuse, which extracts gene fusions that are verified at both the genomic and transcriptomic levels. Apart from the already reported genetic subgroups of osteosarcoma with TP53 structural variants, or MDM2 and/or CDK4 amplification, we did not identify any recurrent genetic driver that signifies the remaining cases. Among the plethora of mutations identified, we found genetic alterations characteristic of, or similar to, those of other bone and soft tissue tumors in 8 cases. These mutations were found in tumors with relatively few other genetic alterations or in adults. Due to the lack of clinical context and available tissue, we can question the diagnosis only on a genetic basis. However, our findings support the notion that osteosarcomas with few chromosomal alterations or adult onset seem genetically distinct from conventional osteosarcomas of children and adolescents.
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| 3. |
- Saba, Karim H., et al.
(författare)
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Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway
- 2023
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Ingår i: Journal of Pathology. - 0022-3417. ; , s. 147-160
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Tidskriftsartikel (refereegranskat)abstract
- TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma.
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