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Rigshospitalet - en del af Københavns Universitetshospital

Functional consequences of structural variants on the 3D architecture of cancer genomes

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

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Structural variation (SV) is a mechanism of genetic variation with significant implications in cancer. Chromosomal rearrangements, such as deletions and translocations, involve up to hundreds of genes and can be used as biomarkers for earlier diagnosis and more accurate prognosis. However, the underlying mechanisms and phenotypic impact of SVs are not well understood. Previous work has correlated the likelihood of SV formation with
tissue-specific genome architecture, but such investigations are limited to a static view on tissue after genomic insult, i.e. tumor tissue that already acquired the genomic aberrations.
To address this issue, we generated an in vitro model system that allows us to induce and track massive genomic rearrangements in the same cell population. We utilize Hi-C, a method developed to identify genomic regions in spatial proximity in the nucleus, to formulate a systematic approach that infers the juxtaposition of the rearranged DNA fragments and produces telomere-to-telomere assemblies of the derivative chromosomes. We leverage that information to identify a feedback mechanism, where chromatin conformation, replication timing, and transcription dictate and are influenced by SV formation.
We extend our investigation to study genomic rearrangements in ~2,700 cancer genomes across 30 tumor types. Our results demonstrate mechanistic and selective forces of SV formation that can be attributed to cell-, histology-, and treatment-induced biases and highlight the importance of studying the cause and consequence of SV in the context of the tissue that they are observed.
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Antal sider119
StatusUdgivet - 4 sep. 2019

ID: 58440880