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Frequent Mutations of Fas Gene in Thyroid Lymphoma¹

Departments of Pathology [T. T., Z. D., H. T., K. A.] and Genetics [S. N.], Osaka University Graduate School of Medicine, Osaka 565-0871, and Section of Surgery, Kuma Hospital, Kobe 650-0011, Japan [F. M.]

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of the Fas gene results in accumulation of lymphoid cells and thus might contribute to lymphomagenesis. Thyroid lymphoma (TL) is supposed to arise from active lymphoid cells formed in the preceding autoimmune chronic lymphocytic thyroiditis (CLTH). We examined the open reading frame of Fas cDNA in 11 cases of CLTH and 26 cases of TL. These patients were admitted to the hospital with varying degrees of goiter. 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. Mutations 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. The insertion of 1 bp (A) at nucleotide 1095 has never been reported in other kinds of malignancies. Thus, this might be unique in TL and CLTH and might be mutational hotspots in these diseases. All mutations occurred in the cytoplasmic region (death domain) known to be involved in the apoptotic signal transduction and thus could be loss-of-function mutations. These findings suggested that accumulation of lymphoid cells in CLTH with Fas mutation provides a basis for development of TL.

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