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Integrative genomic analysis of pediatric osteosarcoma

Ribi, Sebastian. Integrative genomic analysis of pediatric osteosarcoma. 2017, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12166

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Abstract

Osteosarcoma (OS) is the most common malignant tumor of bone, affecting predominantly
children and young adults. Even though modern treatment regimens including pre- and
postoperative multidrug chemotherapy and surgical resection, have additional improved 5
year survival rates to currently 60-70%, no significant improvements have been achieved
in the past decades. Furthermore, the systemic chemotherapy applied lacks specificity and
can lead to severe adverse effects. New targeted cancer treatment approaches, informed by
genomic analysis, aim to exploit molecular properties specific to the neoplastic cells. However,
the genomic landscape of OS is complex and is characterized by chromosomal instability,
which has historically confounded driver gene discovery. While few and small previous
genomic studies exist, a higher sample number and state of the art analysis methods can
contribute to a more complete picture of recurring and driving events. To this end, we first
characterized the genomes of OS using high-throughput sequencing and single nucleotide
polymorphism arrays. We found features of TP53 intron 1 rearrangements suggesting a
highly specific mechanism correlated with transcription. Screening of 288 OS and 1'090 other
tumor types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were
detected in residual tumors, indicating high specificity to OS. Further, we identified a TP53
intron 1 rearrangement as the causal aberration in a four-generation Li-Fraumeni syndrome
family and showed that this rearrangement can at least partially explain the diagnostic
gap of formerly classified “TP53 wild-type” Li-Fraumeni syndrome. We then sequenced the
exomes of 31 OS and integrated the findings with the corresponding sequencing and single
nucleotide polymorphism array data from a replication set of 92 tumors. We identified 14
main driver genes, including some which were formerly unknown in the context of OS. More
than 80% of analyzed tumors furthermore exhibited a specific combination of single-base
substitutions, LOH, or large-scale genome instability signatures which are characteristic of
BRCA1/2-deficient tumors. These BRCA-like traits might be of therapeutic potential since
they could render the tumor cells susceptible to PARP inhibitor treatment, which might
constitute a novel therapeutic strategy to support current chemotherapy regimens. Last,
we screened 337 OS patients for germline alterations and identified bona fide pathogenic
mutations in the RET proto-oncogene in 2% of cases. These mutations appear to combine
functional kinase activity with dysfunctional ligand binding and expose affected individuals
to an increased risk of developing OS when compared to the normal population (odds ratio
9.12). Our findings add OS to the spectrum of RET associated diseases and highlight RET as
a potential target for multi-targeted tyrosine kinase inhibitors.
Advisors:Hynes, Nancy E. and Baumhoer, Daniel and Heinimann, Karl
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
UniBasel Contributors:Heinimann, Karl
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12166
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (xii, 164 Seiten)
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:52
Deposited On:19 Jul 2017 12:17

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