Enteropathy-associated T-cell lymphoma: molecular clonal evolution and its clinical consequences

Refractory celiac disease (RCD) is a rare complication of celiac disease and bears a high risk for lifethreatening enteropathy-associated T-cell lymphoma (EATL). While RCD is generally considered a direct EATL precursor, supporting evidence is limited and the predictive value for EATL development of molecular aberrations in RCD as risk factors unclear. We aim to dissect the clonal evolution of RCD and EATL to support molecular diagnostics-based clinical decision making. RCD specimens of patients with (n=6) and without (n=21) development of EATL within 5 years after diagnosis, and EATL specimens (n=13) with their paired adjacent small cell lymphocytosis (ASCL) in the vicinity of the tumor were used for mutation and copy-number aberrations analysis using nextgeneration sequencing (NGS). In addition, NGS-based T-cell receptor (TR) clonotype analysis for 11 EATL/ASCL pairs was performed. Clonal evolutionary models were inferred and associations of genetic alterations in RCD to EATL risk assessed. Integrated TR gene rearrangement and mutation profiles for 10/11 EATL and ASCL sample pairs shows mixed clonally shared and independent T-cell populations. Only in 2/5 EATL/RCD pairs, a related precursor population was demonstrated. Genetic aberrations were observed in 19/27 duodenal RCD samples irrespective of progression to EATL and in both RCD1 and RCD2. EATL develops via parallel subclonal evolution and selection from a pool of locally residing jejunal Tcell populations with a restricted TR repertoire and a heterogeneous genetic makeup, but not necessarily from RCD populations in the duodenum. These findings provide leads for modifying current clinical decision-making for RCD and EATL patients.