Genomic Characterization of Adolescent and Young Adult Cancers: Investigation of Ewing Sarcoma Susceptibility and Chornobyl Thyroid Tumors

<p>Adolescent and young adult (AYA) cancers, diagnosed between the ages of 15 and 39, can exhibit distinctive genetic and molecular characteristics. Reported epidemiologic findings and treatment outcomes based on pediatric and adult cancer studies are often not suitable for application to the AYA population, underscoring the need for more thorough genomic research. Advances in sequencing technologies have enabled comprehensive analyses of complex genomic characteristics of AYA cancers, crucial for understanding the underlying biology of these malignancies. Here, I have utilized advanced sequencing techniques and integrated analytic approaches to describe important genomic features in two different AYA cancer types: Ewing Sarcoma (EwS) and papillary thyroid carcinoma (PTC). In the EwS study, we describe the interplay between a somatic driver, EWSR1- FLI1, and a highly polymorphic GGAA microsatellite in the 6p25.1 EwS GWAS susceptibility locus, employing third generation long-read sequencing to explore the functional consequences of how the germline informs somatic alterations. We found that longer GGAA repeats residing at 6p25.1 could act as a <em>de novo</em>enhancer in the presence of EWSR1-FLI1 and confer an increase in EwS risk through enhanced binding affinity with EWSR1-FLI1 fusion protein and upregulation of <em>RREB1</em>, which, in turn, increases EwS cell proliferation and potentially DNA replication. In the PTC study, we successfully profiled the somatic mutational landscape and provide insights into regional metastasis in cervical lymph nodes, the most common site in PTC in relatively young patients, effectively bridging the gap between previous pediatric PTC metastasis research and the predominantly older adult PTC cases reported in the TCGA study. Through the integration of multidimensional genomic sequencing data with detailed patient, clinical, and epidemiological information, PTC drivers were identified as the dominant factor associated with regional lymph node metastasis. Our analysis at the transcriptomic level identified overexpression of the HOXC cluster with PTC regional metastasis cases compared to primary PTC. Lastly, I have comprehensively characterized the deletion of chromosome 22 q arm PTC, the most frequent somatic copy number alteration observed, across various genomic studies with different sequencing data. Utilizing cross-study comparisons and pooled analyses, we have identified that the chromosome 22q deletion acts potentially as a cofactor with RAS mutations in PTC tumorigenesis, mediated through immune-related disruption. The findings in this dissertation describe unique genomic features present in AYA cancers and unravel the complex interplay of molecular and epidemiological characteristics that differentiate these cancers from those occurring in other age groups. These insights can potentially be foundation for subsequent translation to clinical applications such as in the development of prognostic biomarkers, AYA cancer risk stratification, and therapeutic strategies tailored to this population.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Lee, Olivia
• <p>0000-0001-5389-6267</p>

Contributors dc:contributor

• John Weinstein, MD PhD
• Stephen Chanock, MD
• Mitchell Machiela, ScD, MPH

• Cancer Genomics
• Bioinformatics
• Genetic Epidemiology
• Adolescent and Young Adult Cancers
• Cancer Biology
• Genetics
• Genomics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1322

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2379