The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis

Lymphomas were studied in kindreds with autoimmune lymphoproliferative synd rome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis us ually associated with germline Fas mutations. Fas (CD95/APO-1) isa ceil sur face receptor that initiates programmed cell death, or apoptosis, of activa ted lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow c ytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), an d the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 membe rs of 39 families, 130 individuals possessed heterozygous germline Fas muta tions. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoprolif eration was first documented. Their risk of non-Hodgkin and Hodgkin lymphom as, respectively, was 14 and 51 times greater; than expected (each P < .001 ). Investigation of these 10 patients and their relatives with Fas mutation s revealed that all had defective lymphocyte apoptosis and most had other f eatures of ALPS. The tumor cells retained the heterozygous Fas mutations fo und in the peripheral blood and manifested defective Fas-mediated killing, These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas, Inherited defects in receptor-mediated lymphocyte ap optosis represents newly appreciated risk factor for lymphomas, (C) 2001 by The American Society of Hematology.