Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas

Ryan D Morin, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Rebecca L Johnston, Lauren Chong, Jasleen Grewal, Stephen Yu, Daniel Fornika, Kevin Bushell, Torsten Holm Nielsen, Tina Petrogiannis-Haliotis, Michael Crump, Axel Tosikyan, Bruno M Grande, David MacDonald, Caroline Rousseau, Maryam Bayat, Pierre Sesques, Remi FromentMarco Albuquerque, Yury Monczak, Kathleen Klein Oros, Celia Greenwood, Yasser Riazalhosseini, Madeleine Arseneault, Errol Camlioglu, André Constantin, Qiang Pan-Hammarstrom, Roujun Peng, Koren K Mann, Nathalie A Johnson

170 Citationer (Scopus)

Abstract

PURPOSE: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.

EXPERIMENTAL DESIGN: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.

RESULTS: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.

CONCLUSIONS: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 1-11. ©2015 AACR.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
ISSN1078-0432
DOI
StatusUdgivet - 8 dec. 2015
Udgivet eksterntJa

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