TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals
TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals
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DOI：
10.3324/haematol.2009.011536
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发表时间：
2010-01-01
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影响因子：
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通讯作者：
Cross, Nicholas C. P.
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文献类型：
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作者：
Chase, Andrew;Ernst, Thomas;Cross, Nicholas C. P.
背景融合基因的形成通过促进新功能的获得而在肿瘤发生和进化中发挥作用。在这里，我们描述了与拷贝数变异相关的两个不相关基因的人类多态性框内融合的第一个例子。设计和方法阵列比较基因组杂交用于鉴定隐秘的致癌融合基因。使用分子生物学和计算方法检查融合基因的结构和起源。使用 PopGen 队列检查表型关联性。结果通过靶向阵列比较基因组杂交来鉴定非典型骨髓增生性肿瘤患者中隐秘的致癌融合基因，鉴定出 TRK 融合基因（TFG，淋巴瘤和甲状腺肿瘤易位靶点）内带有断点的 111 kb 扩增，并且 G 蛋白偶联受体 128 (GPR128) 导致表达框内 TFG-GPR128 融合转录本。该融合基因也在健康个体中以 0.02 (3/120) 的频率被发现。通常，两个基因的方向相同，TFG 紧邻 GPR128 下游。在具有拷贝数变异扩增的个体中，在两个亲本基因之间发现一个或两个 TFG-GPR128 融合拷贝。这些断点共享一个微同源区域，单倍型和微卫星分析表明单个祖先起源。 PopGen 队列分析显示没有明显的表型关联。对 EST 数据库的计算机搜索没有发现其他拷贝数变异扩增相关的融合转录本，表明这是一个不常见的事件。 结论在健康个体中发现多态性基因融合，使人类基因组变异的复杂性又增加了一层，并强调了仔细区分肿瘤样本中发现的致癌变化与非致病性正常变异的重要性。
BackgroundThe formation of fusion genes plays roles in both oncogenesis and evolution by facilitating the acquisition of novel functions. Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant.Design and MethodsArray comparative genomic hybridization was used to identify cryptic oncogenic fusion genes. Fusion gene structure and origin was examined using molecular biological and computational methods. Phenotype associations were examined using PopGen cohorts.ResultsTargeted array comparative genomic hybridization to identify cryptic oncogenic fusion genes in patients with atypical myeloproliferative neoplasms identified a 111 kb amplification with breakpoints within the TRK-fused gene (TFG, a target of translocations in lymphoma and thyroid tumors) and G-protein-coupled receptor 128 (GPR128) resulting in an expressed in-frame TFG-GPR128 fusion transcript. The fusion gene was also identified in healthy individuals at a frequency of 0.02 (3/120). Normally both genes are in identical orientations with TFG immediately downstream of GPR128. In individuals with a copy number variant amplification, one or two copies of the TFG-GPR128 fusion are found between the two parental genes. The breakpoints share a region of microhomology, and haplotype and microsatellite analysis indicate a single ancestral origin. Analysis of PopGen cohorts showed no obvious phenotype association. An in silico search of EST databases found no other copy number variant amplification-associated fusion transcripts suggesting that this is an uncommon event.ConclusionsThe finding of a polymorphic gene fusion in healthy individuals adds another layer to the complexity of human genome variation and emphasizes the importance of careful discrimination of oncogenic changes found in tumor samples from non-pathogenic normal variation.