Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Abstract

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. <i>SETD2</i> was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in <i>STAT5B</i> as well as <i>JAK1</i>, <i>JAK3</i>, <i>STAT3</i>, and <i>SOCS1</i> We also identified mutations in <i>KRAS</i>, <i>TP53</i>, and <i>TERT</i> Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.