Research Papers:
Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets
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Abstract
Elena Mata1,*, Antonio Díaz-López1,*, Ana M. Martín-Moreno1, Margarita Sánchez-Beato2, Ignacio Varela3, María J. Mestre4, Carlos Santonja5, Fernando Burgos6, Javier Menárguez7, Mónica Estévez8, Mariano Provencio2, Beatriz Sánchez-Espiridión9, Eva Díaz1, Carlos Montalbán8, Miguel A. Piris5 and Juan F. García1
1Department of Pathology and Translational Research, MD Anderson Cancer Center Madrid, Madrid, Spain
2Lymphoma Research Group, Medical Oncology Department, Instituto Investigación Sanitaria Puerta de Hierro (IDIPHIM), Madrid, Spain
3Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), Santander, Spain
4Department of Pathology, Hospital Universitario de Móstoles, Madrid, Spain
5Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain
6Department of Pathology, Hospital Severo Ochoa, Madrid, Spain
7Department of Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
8Department of Hematology, MD Anderson Cancer Center Madrid, Madrid, Spain
9Department of Molecular Translational Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*These authors have contributed equally to this work
Correspondence to:
Juan F. García, email: [email protected]
Keywords: mutational analysis; Hodgkin lymphoma; B-cell receptor; BTK; therapeutic target
Received: August 31, 2017 Accepted: November 13, 2017 Published: November 30, 2017
ABSTRACT
Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells.
Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease.
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PII: 22799