Abstract
BackgroundHuman T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL) in a proportion of infected individuals after a long latency period. Development of ATL is a multistep clonal process that can be investigated by monitoring the clonal expansion of HTLV-1-infected cells by isolation of provirus integration sites. The clonal composition (size, number, and combinations of clones) during the latency period in a given infected individual has not been clearly elucidated.MethodsWe used high-throughput sequencing technology coupled with a tag system for isolating integration sites and measuring clone sizes from 60 clinical samples. We assessed the role of clonality and clone size dynamics in ATL onset by modeling data from high-throughput monitoring of HTLV-1 integration sites using single- and multiple-time-point samples.ResultsFrom four size categories analyzed, we found that big clones (B; 513–2048 infected cells) and very big clones (VB; >2048 infected cells) had prognostic value. No sample harbored two or more VB clones or three or more B clones. We examined the role of clone size, clone combination, and the number of integration sites in the prognosis of infected individuals. We found a moderate reverse correlation between the total number of clones and the size of the largest clone. We devised a data-driven model that allows intuitive representation of clonal composition.ConclusionsThis integration site-based clonality tree model represents the complexity of clonality and provides a global view of clonality data that facilitates the analysis, interpretation, understanding, and visualization of the behavior of clones on inter- and intra-individual scales. It is fully data-driven, intuitively depicts the clonality patterns of HTLV-1-infected individuals and can assist in early risk assessment of ATL onset by reflecting the prognosis of infected individuals. This model should assist in assimilating information on clonal composition and understanding clonal expansion in HTLV-1-infected individuals.
Highlights
Clonal expansion in neoplasms is accepted as a general feature of a broad range of tumors and has been addressed from different perspectives [1,2,3,4,5]
adult T cell leukemia (ATL) is a unique neoplasm that is directly caused by infection with human T cell leukemia virus type 1 (HTLV-1) and manifests after a long latency period [8,9,10,11]
Overview of analyzed samples and results We used clonality data from 60 samples derived from cross-sectional and longitudinal analyses of HTLV-1infected individuals
Summary
Clonal expansion in neoplasms is accepted as a general feature of a broad range of tumors and has been addressed from different perspectives [1,2,3,4,5]. By taking advantage of next-generation sequencing (NGS) technology, researchers have devised two main methods, shear sites [14] and tag systems [15], for highthroughput analysis of clonality based on provirus integration sites. These methods enable an improved understanding of genome-wide integration sites and open up new avenues to quantify clone sizes [14, 15, 20, 24,25,26,27]. The clonal composition (size, number, and combinations of clones) during the latency period in a given infected individual has not been clearly elucidated
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