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 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

Fuzzy Clusterwise Generalized Structured Component Analysis

generalized structured component analysis, fuzzy clustering, respondent heterogeneity, alternating least squares, latent curve models, alcohol use,

How specific are executive functioning deficits in attention deficit hyperactivity disorder and autism?

Background: The objective of this study is to identify intact and deficient cognitive processes in children with attention deficit hyperactivity disorder (ADHD) and children with high functioning autism (HFA). Method: Three rigorously diagnosed groups of children aged between 6 and 12 years (54 ADHD, 41 HFA, and 41 normal controls) were tested on a wide range of tasks related to five major domains of executive functioning (EF): inhibition, visual working memory, planning, cognitive flexibility, and verbal fluency. In addition, the role of comorbid oppositional defiant disorder (ODD) and comorbid conduct disorder (CD) in ADHD was investigated by directly comparing 20 children with ADHD and 34 children with comorbid ADHD + ODD/CD. Results: ADHD was associated with EF deficits in inhibiting a prepotent response and verbal fluency. Children with HFA demonstrated deficits in all EF domains, except interference control and working memory. The HFA group showed more difficulties than the ADHD group with planning and cognitive flexibility. The comorbid ADHD + ODD/CD group did not show a distinctive pattern of performance on the EF tests compared to the ADHD group. Conclusion: The present study indicates that children with HFA exhibit more generalised and profound problems with EF tasks compared to children with ADHD. © Association for Child Psychology and Psychiatry, 2004