TIRAP p.R81C is a novel lymphoma risk variant which enhances cell proliferation via NF-κB mediated signaling in B-cells
Regula Burkhard,
Irene Keller,
Miroslav Arambasic,
Darius Juskevicius,
Alexandar Tzankov,
Pontus Lundberg,
Rémy Bruggmann,
Stephan Dirnhofer,
Ramin Radpour,
Urban Novak
Affiliations
Regula Burkhard
Department of Medical Oncology, Inselspital, Bern University Hospital;Division of Experimental Pathology, Institute of Pathology, University of Bern;Department for BioMedical Research (DBMR), University of Bern
Irene Keller
Interfaculty Bioinformatics Unit, Department for BioMedical Research, and Swiss Institute of Bioinformatics, University of Bern
Miroslav Arambasic
Department of Medical Oncology, Inselspital, Bern University Hospital;Division of Experimental Pathology, Institute of Pathology, University of Bern;Department for BioMedical Research (DBMR), University of Bern
Darius Juskevicius
Institute of Pathology and Medical Genetics, University of Basel
Alexandar Tzankov
Institute of Pathology and Medical Genetics, University of Basel
Pontus Lundberg
Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel
Rémy Bruggmann
Interfaculty Bioinformatics Unit, Department for BioMedical Research, and Swiss Institute of Bioinformatics, University of Bern
Stephan Dirnhofer
Institute of Pathology and Medical Genetics, University of Basel
Ramin Radpour
Department of Medical Oncology, Inselspital, Bern University Hospital;Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Switzerland
Urban Novak
Department of Medical Oncology, Inselspital, Bern University Hospital;Department for BioMedical Research (DBMR), University of Bern
Diffuse large B-cell lymphoma is the most common malignant lymphoma in adults. By gene-expression profiling, this lymphoma is divided in three cell-of-origin subtypes with distinct molecular and clinical features. Most lymphomas arise sporadically, yet familial clustering is known, suggesting a genetic contribution to disease risk. Familial lymphoma cases are a valuable tool to investigate risk genes. We studied a Swiss/Japanese family with 2 sisters affected by a primary mediastinal B-cell lymphoma and a non-germinal center diffuse large B-cell lymphoma not otherwise specified, respectively. The somatic landscape of both lymphomas was marked by alterations affecting multiple components of the JAK-STAT pathway. Consequently, this pathway was constitutively activated as evidenced by high pJAK2 as well as increased nuclear pSTAT3 and pSTAT6 in malignant cells. Potential lymphoma risk variants were identified by whole exome sequencing of the germline DNA derived from siblings and unaffected family members. This analysis revealed a pathogenic variant in TIRAP, an upstream regulator of NF-κB, in both affected siblings and their mother. We observed increased B-cell proliferation in family members harboring the TIRAP p.R81C variant. B-cell proliferation correlated with TIRAP and NF-κB target gene expression, suggesting enhanced NF-κB pathway activity in TIRAP p.R81C individuals. TIRAP knockdown reduced B-cell survival and NF-κB target gene expression, particularly in individuals with TIRAP p.R81C. Functional studies revealed significantly increased NF-κB activity and resistance to stress-induced cell-death by TIRAP p.R81C. The identification of an inherited TIRAP variant provides evidence for a novel link between genetic alterations affecting the NF-κB pathway and lymphomagenesis.
