Somatic Fas Mutations in Non-Hodgkin's Lymphoma: Association With Extranodal Disease and Autoimmunity

Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syn- drome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identi- fied in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant- negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with so- matic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreac- tive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmu- nity. r 1998 by The American Society of Hematology. exists between NHL and autoimmune disease. Patients with autoimmune diseases, including systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, and autoimmune thyroid disease, have an increased risk for hemato- poietic cancers, in particular lymphoma, 11-13 and T-cell-rich B-cell (TRB) lymphoma and Hodgkin's disease have been reported in patients with ALPS. 9 Conversely, approximately 8% of patients with NHL exhibit autoimmune phenomena. 14 Here we show that 11% of sporadic NHL harbor Fas mutations, and that the majority of patients with Fas-mutated lymphomas present with extranodal disease and clinical features suggestive of autoreactive disease.