title: The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.
abstract: Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found 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 apoptosis represent a newly appreciated risk factor for lymphomas.
authors: Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. sstraus@nih.gov
authors: S E
authors: SE
authors: Straus
authors: E S
authors: ES
authors: Jaffe
authors: J M
authors: JM
authors: Puck
authors: J K
authors: JK
authors: Dale
authors: K B
authors: KB
authors: Elkon
authors: A
authors: A
authors: Rösen-Wolff
authors: A M
authors: AM
authors: Peters
authors: M C
authors: MC
authors: Sneller
authors: C W
authors: CW
authors: Hallahan
authors: J
authors: J
authors: Wang
authors: R E
authors: RE
authors: Fischer
authors: C E
authors: CE
authors: Jackson
authors: A Y
authors: AY
authors: Lin
authors: C
authors: C
authors: Bäumler
authors: E
authors: E
authors: Siegert
authors: A
authors: A
authors: Marx
authors: A K
authors: AK
authors: Vaishnaw
authors: T
authors: T
authors: Grodzicky
authors: T A
authors: TA
authors: Fleisher
authors: M J
authors: MJ
authors: Lenardo
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001327:Autoimmune Diseases / Q000150:complications* / Q000235:genetics; D002648:Child; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008214:Lymphocytes / Q000473:pathology; D008223:Lymphoma / Q000209:etiology* / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000150:complications* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D019014:fas Receptor / Q000235:genetics* / Q000494:pharmacology
chemical_list: D019014:fas Receptor