ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances
ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances
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DOI：
10.1182/blood.v99.1.238
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发表时间：
2002-01-01
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：
Camacho, E;Hernández, L;Campo, E
共济失调-毛细血管扩张症突变（ATM）基因编码一种蛋白质，该蛋白质与细胞对DNA损伤的反应密切相关。ATM的改变已被观察到在一些散发性淋巴组织增生性疾病。在套细胞淋巴瘤（MCL）中发现的反复发生的11 q22 -23缺失提示ATM在这些淋巴瘤中可能失活。在这项研究中，ATM基因的改变和蛋白表达进行了检查，分别在20和17 MCL肿瘤标本。在此之前，这些患者已经检查了p53和p14（ARF）基因状态，并通过比较基因组杂交进行了分析。9例患者有11 q22 -23丢失。在7例患者中检测到8种ATM基因突变。这些改变是磷脂酰肌醇-3激酶（PI-3 K）结构域中的3个错义突变和5个截短突变，包括3个移码、1个无义突变和1个初始甲硫氨酸取代。所有截短突变均与蛋白表达缺失相关。体细胞起源证明在3个突变，而一个突变进行异源性在患者生殖系。ATM失活的典型MCL的染色体不平衡（7.8 +/- 1.3）显著高于野生型基因的肿瘤（3 +/- 1.1）（P = 0.001）。此外，具有双等位基因ATM改变的肿瘤与3q增益（P = 0.015）和频繁的淋巴结受累（P = 0.049）相关。ATM基因改变与肿瘤的组织学变异、p53/p14（ARF）基因状态、患者生存率或其他临床病理特征无关。这些结果表明，ATM基因突变在MCL主要是截断或错义突变涉及PI-3 K结构域，并可能发挥作用，在这些肿瘤的一个子集与染色体不平衡的数量增加的发病机制。
The ataxia-telangiectasia mutated (ATM) gene codifies for a protein critically involved in the cellular response to DNA damage. ATM alterations have been observed in some sporadic lymphoproliferative disorders. The recurrent 11q22-23 deletions found in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in these lymphomas. In this study, ATM gene alterations and protein expression were examined in 20 and 17 MCL tumor specimens, respectively. Previously, these patients had been examined for p53 and p14(ARF) gene status and analyzed by comparative genomic hybridization. Nine patients had 11q22-23 losses. Eight ATM gene mutations were detected in 7 patients. These alterations were 3 missense mutations in the phosphatidyl-inositol-3 kinase (PI-3K) domain and 5 truncating mutations, including 3 frameshifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were associated with lack of protein expression. Somatic origin was demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were significantly higher in typical MCL with ATM inactivation (7.8 +/- 1.3) than in tumors with the wildtype gene (3 +/- 1.1) (P = .001). Moreover, tumors with bi-allelic ATM alteration were associated with 3q gains (P = .015) and frequent extranodal Involvement (P = .049). ATM gene alterations were not related to the histologic variant of the tumors, p53/p14(ARF) gene status, survival, or other clinicopathologic features of the patients. These findings Indicate that ATM gene mutations In MCL are mainly truncating or missense mutations Involving the PI-3K domain, and that may play a role In the pathogenesis of a subset of these tumors with increased numbers of chromosomal Imbalances.