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Supplementary Methods, Figures S1 - S9 from The Genetic Basis of Hepatosplenic T-cell Lymphoma

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posted on 2023-04-03, 21:24 authored by Matthew McKinney, Andrea B. Moffitt, Philippe Gaulard, Marion Travert, Laurence De Leval, Alina Nicolae, Mark Raffeld, Elaine S. Jaffe, Stefania Pittaluga, Liqiang Xi, Tayla Heavican, Javeed Iqbal, Karim Belhadj, Marie Helene Delfau-Larue, Virginie Fataccioli, Magdalena B. Czader, Izidore S. Lossos, Jennifer R. Chapman-Fredricks, Kristy L. Richards, Yuri Fedoriw, Sarah L. Ondrejka, Eric D. Hsi, Lawrence Low, Dennis Weisenburger, Wing C. Chan, Neha Mehta-Shah, Steven Horwitz, Leon Bernal-Mizrachi, Christopher R. Flowers, Anne W. Beaven, Mayur Parihar, Lucile Baseggio, Marie Parrens, Anne Moreau, Pierre Sujobert, Monika Pilichowska, Andrew M. Evens, Amy Chadburn, Rex K.H. Au-Yeung, Gopesh Srivastava, William W. L. Choi, John R. Goodlad, Igor Aurer, Sandra Basic-Kinda, Randy D. Gascoyne, Nicholas S. Davis, Guojie Li, Jenny Zhang, Deepthi Rajagopalan, Anupama Reddy, Cassandra Love, Shawn Levy, Yuan Zhuang, Jyotishka Datta, David B. Dunson, Sandeep S. Davé

Supplementary Figure S1. Sanger sequencing chromatograms. Supplementary Figure S2. Cancer cell fraction for driver genes. Supplementary Figure S3. Ideogram with chromosome 7 alterations. Supplementary Figure S4. Examples of Exome Copy Number. Supplementary Figure S5. Exploratory Kaplan-Meier plots for clinical covariates. Supplementary Figure S6. Exploratory Kaplan-Meier plots for molecular covariates. Supplementary Figure S7. Sanger and exome sequencing validation of SETD2 biallelic mutation in one HSTL case. Supplementary Figure S8. SETD2 expression in mutant vs. wildtype cases. Supplementary Figure S9. Mutual exclusivity of STAT5B, PIK3CD, and STAT3 mutations.

Funding

NIH

Lymphoma Research Foundation

Hertz Foundation

National Science Foundation

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ARTICLE 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, 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 TP53. SETD2 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. 352.This article is highlighted in the In This Issue feature, p. 339

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    BiomarkersCell SignalingComputational MethodsGene expression profilingEpigeneticsHematological CancersLeukemiasOncogenes & Tumor Suppressors

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