@article{Antonio Vogelsberg_Julia Steinhilber_Barbara Mankel_Birgit Federmann_Janine Schmidt_Ivonne A. Montes-Mojarro_Katrin Hüttl_Maria Rodriguez-Pinilla_Praveen Baskaran_Sven Nahnsen_Miguel A. Piris_German Ott_Leticia Quintanilla-Martinez_Irina Bonzheim_Falko Fend_2021, place={Pavia, Italy}, title={Genetic evolution of <i>in situ</i> follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype}, volume={106}, url={https://haematologica.org/article/view/9914}, DOI={10.3324/haematol.2020.254854}, abstractNote={<p><em>In situ</em> follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified ten paired cases of ISFN and DLBCL/HGBL, including six <em>de novo</em> tumors and four tumors transformed from FL as an intermediate step, and investigated their clonal evolution using microdissection and next-generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or <em>BCL2</em> rearrangements and/or the demonstration of shared somatic mutations for all ten cases. Targeted sequencing revealed <em>CREBBP</em>, <em>KMT2D</em>, <em>EZH2</em>, <em>TNFRSF14</em> and <em>BCL2</em> as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as an intermediate step and that during this progression, branched evolution is common.</p&gt;}, number={10}, journal={Haematologica}, author={Antonio Vogelsberg and Julia Steinhilber and Barbara Mankel and Birgit Federmann and Janine Schmidt and Ivonne A. Montes-Mojarro and Katrin Hüttl and Maria Rodriguez-Pinilla and Praveen Baskaran and Sven Nahnsen and Miguel A. Piris and German Ott and Leticia Quintanilla-Martinez and Irina Bonzheim and Falko Fend}, year={2021}, month={Oct.}, pages={2673-2681} }