title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
abstract: 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, includingSETD2, INO80, andARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations inSTAT5B(31%),STAT3(9%), andPIK3CD(9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events inEZH2, KRAS, andTP53SETD2was the most frequently silenced gene in HSTL. We experimentally demonstrated thatSETD2acts as a tumor suppressor gene. In addition, we found that mutations inSTAT5BandPIK3CDactivate 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 definesSETD2as a tumor suppressor gene in HSTL and implicates genes includingINO80andPIK3CDin 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.
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mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D059472:Exome / Q000235:genetics; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras); D013160:Splenic Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C524421:INO80 protein, human; D016283:Proto-Oncogene Proteins p21(ras)