Oncotarget

Research Papers:

Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

Elena Mata, Antonio Díaz-López, Ana M. Martín-Moreno, Margarita Sánchez-Beato, Ignacio Varela, María J. Mestre, Carlos Santonja, Fernando Burgos, Javier Menárguez, Mónica Estévez, Mariano Provencio, Beatriz Sánchez-Espiridión, Eva Díaz, Carlos Montalbán, Miguel A. Piris and Juan F. García _

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Oncotarget. 2017; 8:111386-111395. https://doi.org/10.18632/oncotarget.22799

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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: jfgarcia@mdanderson.es

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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