Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome

Pierre‐marie Duret (1, 2) , Cedric Schleiss (3) , Lou Kawka (4) , Nicolas Meyer (5) , Tao Ye (6, 7) , Alain Saraux (8, 9) , Valérie Devauchelle‐pensec (8, 9) , Raphaèle Seror (10, 2) , Claire Larroche (11) , Aleth Perdriger (12) , Jean Sibilia (4) , Laurent Vallat (13) , Luc‐matthieu Fornecker (14) , Gaetane Nocturne (15, 10, 2) , Xavier Mariette (10, 2) , Jacques‐eric Gottenberg (16, 4, 3)

1 Hôpitaux Civils de Colmar
2 PN - Projet NECESSITY
3 I2CT - Immunologie, Immunopathologie et Chimie Thérapeutique
4 Service de rhumatologie [Strasbourg]
5 GMRC - Groupe Méthodes en Recherche Clinique [Strasbourg]
6 Plateforme GenomEast [Illkrch]
7 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
8 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies
9 CeRAINO - Centre National de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France
10 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
11 Service de médecine interne [Avicenne]
12 Service de rhumatologie [Rennes] = Rheumatology [Rennes]
13 IRFAC - Inserm U1113 - Interface de Recherche Fondamentale et Appliquée en Cancérologie
14 ICANS - Institut de Cancérologie de Strasbourg Europe
15 Université Paris-Saclay
16 IBMC - Institut de biologie moléculaire et cellulaire

Objective. We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL). Methods. Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. Results. Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. Conclusion. BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.

Mots clés: sjogren; Syndrome; non-Hodgkin's lymphoma; B-cells

Domaines: Sciences du Vivant [q-bio]

Pierre‐marie Duret, Cedric Schleiss, Lou Kawka, Nicolas Meyer, Tao Ye, et al.. Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome. Arthritis & rheumatology, 2023, 75 (10), pp.1798-1811. ⟨10.1002/art.42550⟩. ⟨inserm-04176586⟩