Exploring the genetic landscape in cutaneous T-cell lymphoma with short- and long-read sequencing

Exploring the genetic landscape in cutaneous T-cell lymphoma with short- and long-read sequencing<br /> Carsten Hain<br /> #### Abstract Cutaneous T-cell lymphoma (CTCL) are a group of diseases with heterogenous genetic alterations. In general, there are recurrent copy-number variants and rare, single nucleotide variants that ultimately cluster in a limited number of pathways, including JAK-STAT- and T-cell receptor signaling. Currently, there is a lack of knowledge about the genetic changes in early and treatment-naïve patients, which makes a correlation between genetics and variable disease progression impossible.<br /> In this work, the copy-number landscape of the rare CTCL subtype, Sézary syndrome, was further detailed using whole-exome sequencing data, and the frequency of whole-genome duplications was determined. Furthermore, molecular timing of large copy-number variants was quantified. Specifically, the STAT5-bearing chr17q amplification arises very early in tumor evolution, which underlines the central function of this signaling pathway. Analysis of samples from the most common CTCL subtype, mycosis fungoides, revealed a low tumor cell fraction in bulk skin biopsies. To tackle this issue, an approach for enrichment of malignant cells was applied. This allowed a more confident calling of somatic variants, especially for copy-number variants. Analysis of mycosis fungoides samples with a high tumor cell fraction revealed a severely altered copy-number landscape. The use of Oxford Nanopore long-read sequencing enabled a precise elucidation of structural variants and uncovered multiple classes of complex structural variants underlying the recurrent losses of common tumor suppressor genes in mycosis fungoides.<br /> In summary, this work contributes to the current understanding of CTCL genetics, highlights the complexities that hinders further progress in uncovering the genetic basis of this disease, and first-time uses third-generation sequencing technologies to unravel the complex genetics of mycosis fungoides.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Universität Bielefeld

Year

2024

Author dc:creator

• Hain, Carsten

Repository record source_url

https://pub.uni-bielefeld.de/record/2987114

OAI identifier oai:identifier

oai:pub.uni-bielefeld.de:2987114