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Decoding Genetic Enigmas in Sarcoma

Difilippo, Valeria LU (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate professor Pillay, Nischalan, University College London Cancer Institute, London, UK
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:60
pages
100 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2024-05-16 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-553-4
language
English
LU publication?
yes
id
107cc4b6-4ea0-423c-bb4a-58c6012d62cf
date added to LUP
2024-04-10 13:27:38
date last changed
2024-04-26 13:53:36
@phdthesis{107cc4b6-4ea0-423c-bb4a-58c6012d62cf,
  abstract     = {{Sarcomas represent a broad and heterogenous group of rare tumors. For some subtypes, there are<br/>pathognomonic genetic alterations available, while for others such alterations remain to be identified.<br/>Especially in entities that harbor large numbers of complex genetic changes, much still remains to be<br/>understood. One such entity is osteosarcoma, the most common primary bone tumor. Although primarily<br/>affecting children and adolescents, this tumor typically presents a chaotic genome. In Papers I-III, we<br/>present different genetic mutational mechanisms that distinguish osteosarcoma sub-entities with different<br/>biology and tumor behavior. Namely, we present a recurrent mechanism involving the promoter region<br/>of the <i>TP53</i> tumor suppressor gene in a subset of conventional osteosarcomas. We demonstrate that<br/>structural variants abrogate <i>TP53</i> expression but also relocate its promoter region. By responding to<br/>ongoing DNA damage, it in turn leads to upregulation of known or putative oncogenes erroneously<br/>translocated into its vicinity. Additionally, we subdivide 12q-amplified osteosarcomas into four distinct<br/>groups and show that recurrent promoter swapping events involving the <i>FRS2</i> and <i>PLEKHA5</i> regulatory<br/>regions occur in many high-grade and dedifferentiated osteosarcomas with <i>CDK4</i> and <i>MDM2</i><br/>amplification. Moreover, we found that osteosarcomas with relatively few chromosomal alterations or<br/>adult onset are genetically heterogenous. Finally, in the last part of the thesis (Papers III-IV), we<br/>introduced new bioinformatics tools: (i) NAFuse to detect gene fusions; (ii) the genomic complexity score<br/>(GCS) to analyze the complexity genome-wide; and (iii) SarcDBase, a tool that integrates genomic and<br/>transcriptomic data with existing information. Collectively, this thesis has advanced our understanding of<br/>the role played by specific mutations in the development and progression of osteosarcoma and has<br/>introduced new bioinformatics tools that facilitate the analysis and interpretation of highly complex<br/>genetic information.}},
  author       = {{Difilippo, Valeria}},
  isbn         = {{978-91-8021-553-4}},
  issn         = {{1652-8220}},
  language     = {{eng}},
  number       = {{2024:60}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Decoding Genetic Enigmas in Sarcoma}},
  url          = {{https://lup.lub.lu.se/search/files/179800414/Thesis_Valeria_Difilippo_LUCRIS.pdf}},
  year         = {{2024}},
}