p16INK4a gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas
p16INK4a gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas
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DOI：
10.1182/blood.v91.8.2977.2977_2977_2984
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发表时间：
1998-04-15
期刊：
影响因子：
20.3
通讯作者：
Campo, E
中科院分区：
文献类型：
--
作者：
Pinyol, M;Cobo, F;Campo, E
侵袭性淋巴瘤的发病机制和惰性变体的组织学转化的分子机制尚不清楚。为了确定p16（INK4a）基因改变在非霍奇金淋巴瘤（NHL）发病机制和惰性变体的组织学进展中的作用，我们分析了该基因在一系列112个NHL中的表达、缺失和突变。该基因的超甲基化也在缺乏蛋白质表达但没有基因突变或缺失的肿瘤亚组中进行了检查，在64例惰性淋巴瘤中的3例（5%）中检测到p16（INK4a）基因改变，但在48例原发性或转化的侵袭性变体中的16例（33%）中检测到。在低度恶性肿瘤中，p16（INK4a）基因突变在1例（4%）慢性淋巴细胞白血病（半合子错义突变）、1例（6%）滤泡性淋巴瘤（纯合子缺失）和1例（5%）典型套细胞淋巴瘤（纯合子缺失）中检出。在侵袭性肿瘤中，2例（29%）Richter综合征中观察到p16（INK4a）基因改变（2例纯合性缺失），3例（33%）转化滤泡性淋巴瘤（1例纯合性缺失和2例无义突变），3例（43%）母细胞样套细胞淋巴瘤（2例纯合子和1例半合子缺失），5例（28%）原发大细胞淋巴瘤（1例纯合性缺失和4例高甲基化），2例淋巴母细胞性淋巴瘤（2例纯合性缺失）和1/2例间变性大细胞淋巴瘤（高甲基化）。除了典型的伴半合子点突变的慢性淋巴细胞白血病（CLL）外，所有伴p16（INK4a）改变的肿瘤中蛋白表达均丢失。3例病例的惰性和转化期的连续样品显示在Richter综合征中存在p16（INK4a）缺失，但在2例CLL组分中不存在，而在滤泡性淋巴瘤中，滤泡性肿瘤和弥漫性大细胞淋巴瘤中都存在该缺失。总之，这些研究结果表明，p16（INK4a）基因的改变是一个相对罕见的现象在NHL。然而，缺失，突变，和过度甲基化的基因与蛋白质表达的损失与侵袭性肿瘤，他们也可能参与惰性淋巴瘤的组织学进展。(C)1998年，美国血液学会。
The molecular mechanisms underlying the pathogenesis of aggressive lymphomas and the histological transformation of indolent variants are not well known. To determine the role of p16(INK4a) gene alterations in the pathogenesis of non-Hodgkin's lymphomas (NHLs) and the histological progression of indolent variants, we have analyzed the expression, deletions, and mutations of this gene in a series of 112 NHLs. Hypermethylation of the gene was also examined in a subset of tumors with lack of protein expression but without mutations or deletions of the gene, p16(INK4a) gene alterations were detected in 3 out of 64 (5%) indolent lymphomas but in 16 out of 48 (33%) primary or transformed aggressive variants. In the low-grade tumors, p16(INK4a) alterations were detected in 1 (4%) chronic lymphocytic leukemia (hemizygous missense mutation), 1 (6%) follicular lymphoma (homozygous deletion), and 1 (5%) typical mantle cell lymphoma (homozygous deletion), The two later cases followed an aggressive clinical evolution. In the aggressive tumors, p16(INK4a) gene alterations were observed in 2 (29%) Richter's syndromes (2 homozygous deletions), 3 (33%) transformed follicular lymphomas (1 homozygous deletion and 2 nonsense mutations), 3 (43%) blastoid mantle cell lymphomas (2 homozygous and 1 hemizygous deletions), 5 (28%) de novo large-cell lymphomas (1 homozygous deletion and 4 hypermethylations), 2 lymphoblastic lymphomas (2 homozygous deletions), and 1 of 2 anaplastic large cell lymphomas (hypermethylation). Protein expression was lost in all tumors with p16(INK4a) alterations except in the typical chronic lymphocytic leukemia (CLL) with hemizygous point mutation, Sequential samples of the indolent and transformed phase of three cases showed the presence of p16(INK4a) deletions in the Richter's syndrome but not in the CLL component of two cases, whereas in a follicular lymphoma the deletion was present in both the follicular tumor and in the diffuse large-cell lymphoma. In conclusion, these findings indicate that p16(INK4a) gene alterations are a relatively infrequent phenomenon in NHLs. However, deletions, mutations, and hypermethylation of the gene with loss of protein expression are associated with aggressive tumors and they may also participate in the histological progression of indolent lymphomas. (C) 1998 by The American Society of Hematology.