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Genetic Characterization and Identification of Novel Treatment Targets in Anaplastic Thyroid Carcinoma

Ravi, Naveen LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(117).
Abstract
Anaplastic thyroid cancer (ATC) is a rare and highly aggressive thyroid malignancy, usually resistant to conventional therapeutic strategies. The prognosis of ATC is extremely poor with a median survival rate of 6 months. Current treatment therapy includes surgical resection in combination with external radiotherapy and chemotherapy. The underlying mechanisms involved in ATC tumorigenesis is understudied. In this thesis, we have focused on genomic characterization of ATC that could possibly lead to identification of novel treatment strategies in ATC.

Article I & III highlights the genomic heterogeneity in ATC cell lines and primary cases. ATC displayed massive aneuploidy with frequent variations in copy number. Additionally,... (More)
Anaplastic thyroid cancer (ATC) is a rare and highly aggressive thyroid malignancy, usually resistant to conventional therapeutic strategies. The prognosis of ATC is extremely poor with a median survival rate of 6 months. Current treatment therapy includes surgical resection in combination with external radiotherapy and chemotherapy. The underlying mechanisms involved in ATC tumorigenesis is understudied. In this thesis, we have focused on genomic characterization of ATC that could possibly lead to identification of novel treatment strategies in ATC.

Article I & III highlights the genomic heterogeneity in ATC cell lines and primary cases. ATC displayed massive aneuploidy with frequent variations in copy number. Additionally, we found frequent mutations in TP53, TERT, BRAF and RAS family genes. Furthermore, the most frequent mutational signature in ATC cell lines and primary cases was increased activity of the cytidine deaminase apolipoprotein B editing complex (APOBEC). Moreover, we found interstitial deletions in NEGR1, resulting in aberrant splicing, which could possibly be a driver event in ATC. Furthermore, we detected amplifications in CCNE1, CDK6 and TWIST1; these patients could be treated with targeted therapy. In Article II, we investigated the tumor initiation, progression and clonal evolution of papillary thyroid cancer in a conditional mouse model. Stochastic activation of mutant Braf leads to development of multifocal microtumors that are oligoclonal in nature. Furthermore, we identified additional mutations at low frequencies, highlighting the presence of subclones that might be associated with tumor progression. In article IV, we studied the genome-wide methylation profile in primary ATC cases. Global hypomethylation was common in ATC, while hypermethylation was noticed in promoters and CpG islands. Furthermore, aberrant DNA methylation in MTOR and NOTCH1 genes was associated with increased expression. Alternatively, hypomethylation in thyroid related genes including TSHR and SLC26A7 was associated with decreased expression in gene body regions. Moreover, we found that processes related to the cell cycle were upregulated, while TP53-regulated genes and thyroid-related pathways were downregulated in ATC.

Taken together, this thesis provides a better understanding of the complex processes involved in ATC tumorigenesis. Furthermore, a substantial proportion of ATC patients could be suitable for personalized treatment, including CDK and TWIST1 inhibition therapy.
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author
supervisor
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Anaplastic thyroid cancer, copy number alterations, somatic mutations, mutational signatures, DNA methylation analysis, Gene expression analysis
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
117
pages
68 pages
publisher
Lund University: Faculty of Medicine
ISSN
1652-8220
ISBN
978-91-7619-846-9
language
English
LU publication?
yes
additional info
Date: 2019-11-28 Time: 13:00 Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund External reviewer (s) Name: Helou, Khalil Title: Associate Professor Affiliation: University of Gothenburg
id
b2b10075-1aea-4976-92c0-5798c5163b81
date added to LUP
2019-10-31 11:58:45
date last changed
2019-11-19 13:49:52
@phdthesis{b2b10075-1aea-4976-92c0-5798c5163b81,
  abstract     = {Anaplastic thyroid cancer (ATC) is a rare and highly aggressive thyroid malignancy, usually resistant to conventional therapeutic strategies. The prognosis of ATC is extremely poor with a median survival rate of 6 months. Current treatment therapy includes surgical resection in combination with external radiotherapy and chemotherapy. The underlying mechanisms involved in ATC tumorigenesis is understudied. In this thesis, we have focused on genomic characterization of ATC that could possibly lead to identification of novel treatment strategies in ATC.<br/><br/>Article I &amp; III highlights the genomic heterogeneity in ATC cell lines and primary cases. ATC displayed massive aneuploidy with frequent variations in copy number. Additionally, we found frequent mutations in <i>TP53</i>, <i>TERT</i>, <i>BRAF </i>and <i>RAS </i>family genes. Furthermore, the most frequent mutational signature in ATC cell lines and primary cases was increased activity of the cytidine deaminase apolipoprotein B editing complex (APOBEC). Moreover, we found interstitial deletions in <i>NEGR1</i>, resulting in aberrant splicing, which could possibly be a driver event in ATC. Furthermore, we detected amplifications in <i>CCNE1</i>, <i>CDK6 </i>and <i>TWIST1</i>; these patients could be treated with targeted therapy. In Article II, we investigated the tumor initiation, progression and clonal evolution of papillary thyroid cancer in a conditional mouse model. Stochastic activation of mutant Braf leads to development of multifocal microtumors that are oligoclonal in nature. Furthermore, we identified additional mutations at low frequencies, highlighting the presence of subclones that might be associated with tumor progression. In article IV, we studied the genome-wide methylation profile in primary ATC cases. Global hypomethylation was common in ATC, while hypermethylation was noticed in promoters and CpG islands. Furthermore, aberrant DNA methylation in <i>MTOR </i>and <i>NOTCH1 </i>genes was associated with increased expression. Alternatively, hypomethylation in thyroid related genes including <i>TSHR </i>and <i>SLC26A7 </i>was associated with decreased expression in gene body regions. Moreover, we found that processes related to the cell cycle were upregulated, while TP53-regulated genes and thyroid-related pathways were downregulated in ATC.<br/><br/>Taken together, this thesis provides a better understanding of the complex processes involved in ATC tumorigenesis. Furthermore, a substantial proportion of ATC patients could be suitable for personalized treatment, including CDK and TWIST1 inhibition therapy.<br/>},
  author       = {Ravi, Naveen},
  isbn         = {978-91-7619-846-9},
  issn         = {1652-8220},
  language     = {eng},
  number       = {117},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetic Characterization and Identification of Novel Treatment Targets in Anaplastic Thyroid Carcinoma},
  url          = {https://lup.lub.lu.se/search/ws/files/71276156/Naveen_Ravi_ALL.pdf},
  volume       = {2019},
  year         = {2019},
}