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

Area of Science:

• Gastroenterology
• Oncology
• Immunology

Background:

• Refractory celiac disease (RCD) is a rare complication of celiac disease with a high risk of developing enteropathy-associated T-cell lymphoma (EATL).
• The direct precursor relationship between RCD and EATL is not fully understood, and the predictive value of molecular aberrations in RCD for EATL development remains unclear.

Purpose of the Study:

• To investigate the clonal evolution of RCD and EATL.
• To identify molecular aberrations associated with EATL development in RCD patients.
• To inform molecular diagnostics for improved clinical decision-making in RCD and EATL.

Main Methods:

• Next-generation sequencing (NGS) for mutation and copy-number aberration analysis.
• NGS-based T-cell receptor (TR) clonotype analysis.
• Analysis of RCD, EATL, and adjacent small cell lymphocytosis (ASCL) specimens.

Main Results:

• EATL and ASCL samples showed mixed clonal T-cell populations, with related precursor populations identified in only a minority of EATL/RCD pairs.
• Genetic aberrations were present in most RCD samples, regardless of progression to EATL.
• EATL appears to arise from parallel evolution of jejunal T-cell populations, not necessarily from duodenal RCD populations.

Conclusions:

• EATL development may not directly originate from RCD in the duodenum.
• Findings suggest parallel subclonal evolution from local T-cell populations in the jejunum.
• Results may lead to revised clinical decision-making for RCD and EATL patients.