Schaffner C, Idler I, Stilgenbauer S, Döhner H, Lichter P
Abteilung "Organisation komplexer Genome," Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2773-8. doi: 10.1073/pnas.050400997.
In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in this region. The deleted segment contains the ATM (ataxia telangiectasia mutated) gene. ATM is an interesting candidate as a tumor suppressor gene because constitutive inactivation of the gene predisposes ataxia telangiectasia patients to lymphoid malignancies. To assess the potential involvement of the gene in MCL lymphomagenesis, we performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of them with a deletion of one ATM gene copy, by using single-strand conformation polymorphism analysis of reverse transcription-PCR-amplified mRNA and subsequent DNA sequencing. In all seven cases containing a deletion of one ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in two MCLs that did not contain 11q deletions. Interestingly, in three cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germ-line origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicates that ATM plays a role in the initiation and/or progression of MCL.
在套细胞淋巴瘤(MCL)中,t(11;14)易位被认为是该疾病的细胞遗传学标志。然而,最近已确定染色体区域11q22 - q23的缺失是这类癌症中的常见事件,这表明该区域存在与发病机制相关的肿瘤抑制基因。缺失片段包含ATM(共济失调毛细血管扩张症突变)基因。ATM作为肿瘤抑制基因是一个有趣的候选基因,因为该基因的组成性失活使共济失调毛细血管扩张症患者易患淋巴系统恶性肿瘤。为了评估该基因在MCL淋巴瘤发生中的潜在作用,我们通过对逆转录 - PCR扩增的mRNA进行单链构象多态性分析及随后的DNA测序,对12例散发性MCL病例中的ATM进行了突变分析,其中7例存在一个ATM基因拷贝的缺失。在所有7例含有一个ATM等位基因缺失的病例中,均检测到剩余等位基因中的一个点突变,该突变导致异常的转录剪接、截短或蛋白质改变。此外,在两个不含有11q缺失的MCL中鉴定出双等位基因ATM突变。有趣的是,在分析的3例病例中,肿瘤细胞中检测到的ATM突变在非恶性细胞中不存在,表明它们是体细胞起源而非种系起源。在大多数分析病例中,通过缺失和有害点突变使ATM基因的两个等位基因失活,这表明ATM在MCL的发生起始和/或进展中起作用。