Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone

Karim Saba

Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone

Research output: Thesis › Doctoral Thesis (compilation)

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Abstract

Primary tumours of bone are heterogenous and infrequent neoplasms. Distinguishing between benign, intermediate and malignant entities can in some instances pose a clinical challenge. For some tumour types, there is still much to be learned about the genetic mechanisms that give rise to and drive these tumours forward. With the hope of improving diagnostic accuracy and treatment outcomes on the longer term, this thesis will deal with the genetic mutational mechanisms that characterise the primary osteogenic neoplasms osteoblastoma and osteosarcoma.

In Article I, we show that a subgroup of non-FOS-rearranged, preferentially epithelioid osteoblastomas harbour homozygous loss of the NF2 gene. Additionally, we find a lower proportion of FOS-rearranged cases than previously reported and a high normal cell content.

In Article II, we genetically characterise a rare chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumour of bone. We detect a potentially targetable FN1-FGFR1 gene fusion and homozygous loss of the CDKN2A and DMD genes.

In Article III, an RNA-sequencing screen of conventional osteosarcomas reveals that NTRK fusions are rare and most likely non-functional events.

In Article IV, we demonstrate, for the first time, the existence of a recurrent gain-of-function mechanism involving the promoter region of the TP53 tumour suppressor gene in a subset of conventional osteosarcoma. We show 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.

In Article V, 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.

In conclusion, this thesis will highlight the role chromosome remodelling plays in the development of primary osteogenic tumours of bone.

Original language	English
Qualification	Doctor
Awarding Institution	Department of Laboratory Medicine
Supervisors/Advisors	Hansén Nord, Karolin, Supervisor Staaf, Johan, Assistant supervisor Styring, Emelie, Assistant supervisor
Award date	2020 Nov 20
Place of Publication	Lund
Publisher	Lund University, Faculty of Medicine
ISBN (Print)	978-91-7619-982-4
Publication status	Published - 2020 Nov 20

Bibliographical note

Defence details
Date: 2020-11-20
Time: 09:00
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund
External reviewer(s)
Name: Flanagan, Adrienne M.
Title: professor
Affiliation: University College London Cancer Institute, London, UK

Subject classification (UKÄ)

Medical Genetics
Bioinformatics (Computational Biology)
Cancer and Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Karim_Saba_thesis

4 Article

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway
Saba, K. H., Difilippo, V., Kovac, M., Cornmark, L., Magnusson, L., Nilsson, J., van den Bos, H., Spierings, D. C. J., Bidgoli, M., Jonson, T., Sumathi, V. P., Brosjö, O., Staaf, J., Foijer, F., Styring, E., Nathrath, M., Baumhoer, D. & Nord, K. H., 2024 Feb, In: Journal of Pathology. 262, 2, p. 147-160 14 p.
Research output: Contribution to journal › Article › peer-review

Open Access
Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma
Saba, K. H., Cornmark, L., Hofvander, J., Magnusson, L., Nilsson, J., van den Bos, H., Spierings, D. C. J., Foijer, F., Staaf, J., Brosjö, O., Sumathi, V. P., Lam, S. W., Szuhai, K., Bovée, J. V. M. G., Kovac, M., Baumhoer, D., Styring, E. & Nord, K. H., 2020 Oct, In: Journal of Pathology: Clinical Research. 6, 4, p. 231-237 7 p.
Research output: Contribution to journal › Article › peer-review

Open Access
NTRK fusions in osteosarcoma are rare and non-functional events
Ameline, B., Saba, K. H., Kovac, M., Magnusson, L., Witt, O., Bielack, S., Nathrath, M., Nord, K. H. & Baumhoer, D., 2020 Apr, In: Journal of Pathology: Clinical Research. 6, 2, p. 107-112 6 p.
Research output: Contribution to journal › Article › peer-review

Open Access

Cite this

@phdthesis{86b4a2e926954afbb9a35415a2d779ec,

title = "Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone",

abstract = "Primary tumours of bone are heterogenous and infrequent neoplasms. Distinguishing between benign, intermediate and malignant entities can in some instances pose a clinical challenge. For some tumour types, there is still much to be learned about the genetic mechanisms that give rise to and drive these tumours forward. With the hope of improving diagnostic accuracy and treatment outcomes on the longer term, this thesis will deal with the genetic mutational mechanisms that characterise the primary osteogenic neoplasms osteoblastoma and osteosarcoma.In Article I, we show that a subgroup of non-FOS-rearranged, preferentially epithelioid osteoblastomas harbour homozygous loss of the NF2 gene. Additionally, we find a lower proportion of FOS-rearranged cases than previously reported and a high normal cell content.In Article II, we genetically characterise a rare chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumour of bone. We detect a potentially targetable FN1-FGFR1 gene fusion and homozygous loss of the CDKN2A and DMD genes.In Article III, an RNA-sequencing screen of conventional osteosarcomas reveals that NTRK fusions are rare and most likely non-functional events.In Article IV, we demonstrate, for the first time, the existence of a recurrent gain-of-function mechanism involving the promoter region of the TP53 tumour suppressor gene in a subset of conventional osteosarcoma. We show 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.In Article V, 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.In conclusion, this thesis will highlight the role chromosome remodelling plays in the development of primary osteogenic tumours of bone.",

author = "Karim Saba",

note = "Defence details Date: 2020-11-20 Time: 09:00 Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund External reviewer(s) Name: Flanagan, Adrienne M. Title: professor Affiliation: University College London Cancer Institute, London, UK",

year = "2020",

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language = "English",

isbn = "978-91-7619-982-4",

series = "Lund University, Faculty of Medicine Doctoral Dissertation Series",

publisher = "Lund University, Faculty of Medicine",

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type = "Doctoral Thesis (compilation)",

school = "Department of Laboratory Medicine",

}

TY - THES

T1 - Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone

AU - Saba, Karim

N1 - Defence details Date: 2020-11-20 Time: 09:00 Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund External reviewer(s) Name: Flanagan, Adrienne M. Title: professor Affiliation: University College London Cancer Institute, London, UK

PY - 2020/11/20

Y1 - 2020/11/20

N2 - Primary tumours of bone are heterogenous and infrequent neoplasms. Distinguishing between benign, intermediate and malignant entities can in some instances pose a clinical challenge. For some tumour types, there is still much to be learned about the genetic mechanisms that give rise to and drive these tumours forward. With the hope of improving diagnostic accuracy and treatment outcomes on the longer term, this thesis will deal with the genetic mutational mechanisms that characterise the primary osteogenic neoplasms osteoblastoma and osteosarcoma.In Article I, we show that a subgroup of non-FOS-rearranged, preferentially epithelioid osteoblastomas harbour homozygous loss of the NF2 gene. Additionally, we find a lower proportion of FOS-rearranged cases than previously reported and a high normal cell content.In Article II, we genetically characterise a rare chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumour of bone. We detect a potentially targetable FN1-FGFR1 gene fusion and homozygous loss of the CDKN2A and DMD genes.In Article III, an RNA-sequencing screen of conventional osteosarcomas reveals that NTRK fusions are rare and most likely non-functional events.In Article IV, we demonstrate, for the first time, the existence of a recurrent gain-of-function mechanism involving the promoter region of the TP53 tumour suppressor gene in a subset of conventional osteosarcoma. We show 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.In Article V, 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.In conclusion, this thesis will highlight the role chromosome remodelling plays in the development of primary osteogenic tumours of bone.

AB - Primary tumours of bone are heterogenous and infrequent neoplasms. Distinguishing between benign, intermediate and malignant entities can in some instances pose a clinical challenge. For some tumour types, there is still much to be learned about the genetic mechanisms that give rise to and drive these tumours forward. With the hope of improving diagnostic accuracy and treatment outcomes on the longer term, this thesis will deal with the genetic mutational mechanisms that characterise the primary osteogenic neoplasms osteoblastoma and osteosarcoma.In Article I, we show that a subgroup of non-FOS-rearranged, preferentially epithelioid osteoblastomas harbour homozygous loss of the NF2 gene. Additionally, we find a lower proportion of FOS-rearranged cases than previously reported and a high normal cell content.In Article II, we genetically characterise a rare chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumour of bone. We detect a potentially targetable FN1-FGFR1 gene fusion and homozygous loss of the CDKN2A and DMD genes.In Article III, an RNA-sequencing screen of conventional osteosarcomas reveals that NTRK fusions are rare and most likely non-functional events.In Article IV, we demonstrate, for the first time, the existence of a recurrent gain-of-function mechanism involving the promoter region of the TP53 tumour suppressor gene in a subset of conventional osteosarcoma. We show 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.In Article V, 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.In conclusion, this thesis will highlight the role chromosome remodelling plays in the development of primary osteogenic tumours of bone.

M3 - Doctoral Thesis (compilation)

SN - 978-91-7619-982-4

T3 - Lund University, Faculty of Medicine Doctoral Dissertation Series

PB - Lund University, Faculty of Medicine

CY - Lund

ER -

Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone

Abstract

Bibliographical note

Subject classification (UKÄ)

UN SDGs

Access to Document

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Research output

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway

Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma

NTRK fusions in osteosarcoma are rare and non-functional events

Cite this