The Genetic Basis of Hepatosplenic T-cell Lymphoma

Cancer Discov. 2017 Apr;7(4):369-379. doi: 10.1158/2159-8290.CD-16-0330. Epub 2017 Jan 25.


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 SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD 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.Significance: 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 SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adolescent
  • Adult
  • Aged
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Helicases / genetics*
  • DNA-Binding Proteins
  • Enhancer of Zeste Homolog 2 Protein
  • Exome / genetics
  • Female
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Liver Neoplasms / complications
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Lymphoma, T-Cell / complications
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / pathology
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins p21(ras)
  • Splenic Neoplasms / complications
  • Splenic Neoplasms / genetics*
  • Splenic Neoplasms / pathology
  • Transcription Factors
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Proteins / genetics
  • Young Adult


  • ARID1B protein, human
  • DNA-Binding Proteins
  • KRAS protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • INO80 protein, human
  • Proto-Oncogene Proteins p21(ras)