Frequent mutations of Fas gene in thyroid lymphoma

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signalin g through binding of Fas ligand, Mutation of the Fas gene results in accumu lation of lymphoid cells and thus might contribute to lymphomagenesis. Thyr oid lymphoma (TL) is supposed to arise from active lymphoid cells formed in the preceding autoimmune chronic lymphocytic thyroiditis (CLTH). We examin ed the open reading frame of Fas cDNA in 11 cases of CLTH and 26 cases of T L. These patients were admitted to the hospital with varying degrees of goi ter. All of the CLTH patients were female, with median age of 65 years, and all but five cases of TL were female, with median age of 61 years. Mutatio ns of the Fas gene were detected in 3 (27.3 %) of 11 cases of CLTH and 17 ( 65.4 %) of 26 of TL. The Fas mutations comprised 18 frameshift, 3 missense, and 1 nonsense mutation. Frameshift mutations were caused by insertion of 1 bp (A) at nucleotide 1095 in 10 cases and by lack of exon 8 in 8 cases. T he insertion of 1 bp (A) at nucleotide 1095 has never been reported in othe r kinds of malignancies. Thus, this might be unique in TL and CLTH and migh t be mutational hotspots in these diseases. All mutations occurred in the c ytoplasmic region (death domain) known to be involved in the apoptotic sign al transduction and thus could be loss-of-function mutations. These finding s suggested that accumulation of lymphoid cells in CLTH with Fas mutation p rovides a basis for development of TL.