The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including , and , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in (31%), (9%), and (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in , and was the most frequently silenced gene in HSTL. We experimentally demonstrated that acts as a tumor suppressor gene. In addition, we found that mutations in and activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines as a tumor suppressor gene in HSTL and implicates genes including and in the disease. .