Comino-Méndez Iñaki, Tejera Águeda M, Currás-Freixes María, Remacha Laura, Gonzalvo Pablo, Tonda Raúl, Letón Rocío, Blasco María A, Robledo Mercedes, Cascón Alberto
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cancer Genet. 2016 Jun;209(6):272-7. doi: 10.1016/j.cancergen.2016.04.058. Epub 2016 Apr 26.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are tumors arising from the adrenal medulla and sympathetic/parasympathetic paraganglia, respectively. Approximately 40% of PCCs/PGLs are due to germline mutations in one of 16 susceptibility genes, and a further 30% are due to somatic alterations in 5 main genes. Recently, somatic ATRX mutations have been found in succinate dehydrogenase (SDH)-associated hereditary PCCs/PGLs. In the present study we applied whole-exome sequencing to the germline and tumor DNA of a patient with metastatic composite PCC and no alterations in known PCC/PGL susceptibility genes. A somatic loss-of-function mutation affecting ATRX was identified in tumor DNA. Transcriptional profiling analysis classified the tumor within cluster 2 of PCCs/PGLs (without SDH gene mutations) and identified downregulation of genes involved in neuronal development and homeostasis (NLGN4, CD99 and CSF2RA) as well as upregulation of Drosha, an important gene involved in miRNA and rRNA processing. CpG island methylator phenotype typical of SDH gene-mutated tumors was ruled out, and SNP array data revealed a unique profile of gains and losses. Finally, we demonstrated the presence of alternative lengthening of telomeres in the tumor, probably associated with the failure of ATRX functions. In conclusion, somatic variants affecting ATRX may play a driver role in sporadic PCC/PGL.
嗜铬细胞瘤（PCCs）和副神经节瘤（PGLs）分别起源于肾上腺髓质和交感/副交感神经节。约40%的PCCs/PGLs是由16个易感基因之一的种系突变引起的，另外30%是由5个主要基因的体细胞改变引起的。最近，在琥珀酸脱氢酶（SDH）相关的遗传性PCCs/PGLs中发现了体细胞ATRX突变。在本研究中，我们对一名转移性复合性PCC患者的种系和肿瘤DNA进行了全外显子组测序，该患者已知的PCC/PGL易感基因无改变。在肿瘤DNA中鉴定出一个影响ATRX的功能丧失性体细胞突变。转录谱分析将该肿瘤归类于PCCs/PGLs的第2组（无SDH基因突变），并确定参与神经元发育和内环境稳定的基因（NLGN4、CD99和CSF2RA）下调，以及参与miRNA和rRNA加工的重要基因Drosha上调。排除了SDH基因突变肿瘤典型的CpG岛甲基化表型，SNP阵列数据显示了独特的增减谱。最后，我们证明了肿瘤中端粒的替代性延长，这可能与ATRX功能的缺失有关。总之，影响ATRX的体细胞变异可能在散发性PCC/PGL中起驱动作用。
