FAS (CD95) Mutations Are Rare in Gastric MALT Lymphoma but Occur More Frequently in Primary Gastric Diffuse Large B-Cell Lymphoma

• Published in: The American journal of pathology Vol. 164; no. 3; pp. 1081 - 1089
• Main Authors: Wohlfart, Sabine, Sebinger, David, Gruber, Petra, Buch, Judith, Polgar, Doris, Krupitza, Georg, Rosner, Margit, Hengstschläger, Markus, Raderer, Markus, Chott, Andreas, Müllauer, Leonhard
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2004; ASIP; American Society for Investigative Pathology
• Subjects: Apoptosis - physiology; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; DNA Mutational Analysis; fas Receptor - genetics; Hematologic and hematopoietic diseases; Humans; Investigative techniques, diagnostic techniques (general aspects); Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell, Marginal Zone - genetics; Lymphoma, Large B-Cell, Diffuse - genetics; Medical sciences; Mutation; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Regular; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms - genetics; Transfection; Diffuse; Stomach; Fas antigen; Digestive system; Malignant hemopathy; Large cell lymphoma; Non Hodgkin lymphoma; Anatomic pathology; Primitive; MALT lymphoma; Lymphoproliferative syndrome; Primary; Mutation
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)63195-1

A loss of FAS (CD95) function has been proposed to constitute an important step in early mucosa-associated lymphoid tissue (MALT) lymphoma development and FAS mutations have been recognized in malignant lymphomas, in particular at extranodal sites. Since primary gastric lymphomas frequently exhibit resistance to FAS-mediated apoptosis, we investigated whether FAS is mutated in 18 gastric MALT lymphomas and 28 diffuse large B-cell lymphomas (DLBCL). We detected seven mutations in five lymphomas, one MALT lymphoma and four DLBCL; two DLBCL had two mutations. The MALT lymphoma exhibited a point mutation in the splice donor region of intron 3. Three DLBCL had missense mutations in exon 2, which encodes a signal peptide and a portion of the extracellular FAS ligand-binding domain. One DLBCL carried a point mutation in the splice donor region of intron 8, which would result in exon skipping. Two DLBCL harbored a missense mutation in exon 9, which encodes the intracellular death domain. The two death domain mutations inhibited FAS ligand-induced apoptosis in a dominant-negative mode, when transiently expressed in human T47D breast carcinoma and Jurkat T cells. A signal peptide and an extracellular domain mutation, however, failed to inhibit apoptosis in these transfection assays. They are likely to reduce apoptosis in lymphoma cells solely by a loss of function. In summary, our data show that FAS mutations are rare in primary gastric MALT lymphomas (5.6%) but occur in a subset of primary gastric DLBCL (14.3%) and suggest that these mutations contribute to the pathogenesis of gastric lymphomas by rendering lymphocytes resistant to apoptosis.