Grønbaek K, Straten P T, Ralfkiaer E, Ahrenkiel V, Andersen M K, Hansen N E, Zeuthen J, Hou-Jensen K, Guldberg P
Department of Tumor Cell Biology, Institute of Cancer Biology, Danish Cancer Society; the Departments of Pathology and Hematology, Herlev Hospital; and the Departments of Hematology and Pathology, Rigshospitalet, Copenhagen, Denmark.
Blood. 1998 Nov 1;92(9):3018-24.
Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity.
Fas（APO-1/CD95）是一种参与细胞死亡信号传导的细胞表面受体。Fas基因的种系突变与自身免疫性淋巴增殖综合征相关，并且在多发性骨髓瘤中发现了体细胞Fas突变。我们检测了150例非霍奇金淋巴瘤患者Fas基因的整个编码区和所有剪接位点。总体而言，在16例肿瘤（11%）中发现了突变。受体死亡结构域内的错义突变与野生型等位基因的保留相关，表明存在显性负性机制，而死亡结构域外的错义突变与等位基因缺失相关。在3例（60%）黏膜相关淋巴组织型淋巴瘤、9例（21%）弥漫性大B细胞淋巴瘤、2例（6%）滤泡中心细胞淋巴瘤、1例（50%）间变性大细胞淋巴瘤以及1例对皮肤有明显嗜性的不典型B细胞慢性淋巴细胞白血病病例中发现了Fas突变。在16例有体细胞Fas突变的患者中，15例在初诊时表现为结外病变，6例在结外区域复发。13例可评估患者中有10例表现出提示自身反应性疾病的特征。我们的数据表明，Fas的体细胞破坏可能在某些淋巴瘤的发病机制中起作用，并提示Fas突变、癌症和自身免疫之间存在联系。
