PUB - Publikationen an der Universität Bielefeld

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