A COMPREHENSIVE ANALYSIS OF MUTATIONS IN CANCERS AND NEURODEVELOPMENTAL DISORDERS

Date

2023-6-5

Author

Yavuz, Bengi Ruken

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A multitude of pathologies are driven by mutations, and even a single mutation can act as a prognostic marker and modify the global genome and protein expression, thus changing oncogenic signaling pathways. However, a single-driver mutation's contribution to the activation of oncogenic signaling pathways is minimal and necessitates additional mutations over time. This thesis aims to identify co-occurring mutations in genes that promote tumorigenesis and alter the response to treatments. To achieve this, we employed a statistical technique to identify significantly co-occurring mutations in pan-cancer cohorts, focusing on the identification of latent driver mutations with minor observable translational potential and low frequencies. We then discovered 4352 significant different gene double mutations that alter non-redundant pathways and interactions and promote cancer-specific tumorigenesis. Rare co-occurring in trans combinations can serve as metastasis markers, whereas excluded combinations may give rise to oncogene-induced senescence (OIS). Furthermore, this thesis investigates the shared and distinguishing features between neurodevelopmental disorders (NDDs) and cancer. Despite the differences in their clinical manifestations, individuals with NDDs are more likely to develop cancer. Cancer mutations are sporadic and arise during life, whereas NDDassociated mutations are germline. However, both NDDs and cancer share proteins, pathways, and mutations. Deep patterns that are rare but can prompt dramatic phenotypic alterations and serve as clinical signatures can be discovered through interrogating large genomic data and integrating it with small-molecule sensitivity data.

Subject Keywords

mutation doublets, molecular signatures of cancer, latent drivers, cancer genome analysis, neurodevelopmental disorders

URI

https://hdl.handle.net/11511/104180

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Graduate School of Informatics, Thesis