INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France.
Hum Mol Genet. 2012 Dec 15;21(26):5397-405. doi: 10.1093/hmg/dds374. Epub 2012 Sep 6.
Germline mutations in the RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, NF1 or VHL genes are identified in about 30% of patients with pheochromocytoma or paraganglioma and somatic mutations in RET, VHL or MAX genes are reported in 17% of sporadic tumors. In the present study, using mutation screening of the NF1 gene, mapping of chromosome aberrations by single nucleotide polymorphism (SNP) array, microarray-based expression profiling and immunohistochemistry (IHC), we addressed the implication of NF1 somatic alterations in pheochromocytomas and paragangliomas. We studied 53 sporadic tumors, selected because of their classification with RET/NF1/TMEM127-related tumors by genome wide expression studies, as well as a second set of 11 independent tumors selected on their low individual levels of NF1 expression evaluated by microarray. Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases. Gene expression signature of NF1-related tumors highlighted the downregulation of NF1 and the major overexpression of SOX9. Among the second set of 11 tumors, two sporadic tumors carried somatic mutations in NF1 as well as in another susceptibility gene. These new findings suggest that NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma and strengthen the new concept of molecular-based targeted therapy for pheochromocytoma or paraganglioma.
在嗜铬细胞瘤或副神经节瘤患者中，约 30%存在 RET、SDHA、SDHAF2、SDHB、SDHC、SDHD、MAX、TMEM127、NF1 或 VHL 基因的种系突变，而在散发性肿瘤中，RET、VHL 或 MAX 基因的体细胞突变报道为 17%。在本研究中，我们通过 NF1 基因突变筛查、单核苷酸多态性 (SNP) 芯片染色体畸变作图、基于微阵列的表达谱分析和免疫组织化学 (IHC)，研究了 NF1 体细胞改变在嗜铬细胞瘤和副神经节瘤中的意义。我们研究了 53 例散发性肿瘤，这些肿瘤是通过全基因组表达研究分类为 RET/NF1/TMEM127 相关肿瘤的，以及另一组 11 例独立肿瘤，这些肿瘤是根据微阵列评估的 NF1 表达水平低而选择的。肿瘤 DNA 中 NF1 基因的直接测序确定了在分析的 61 例散发性肿瘤中存在 41%（25/61）的失活 NF1 体细胞突变，其中 84%（21/25）的病例存在野生型等位基因丢失。NF1 相关肿瘤的基因表达特征突出了 NF1 的下调和 SOX9 的主要过表达。在第二组 11 例肿瘤中，2 例散发性肿瘤同时携带 NF1 和另一个易感性基因的体细胞突变。这些新发现表明，NF1 功能丧失是散发性嗜铬细胞瘤发生的常见事件，并加强了针对嗜铬细胞瘤或副神经节瘤的基于分子的靶向治疗的新概念。
