Department of Surgical, Uppsala University, 75185 Uppsala, Sweden.
J Clin Endocrinol Metab. 2013 Jul;98(7):E1266-71. doi: 10.1210/jc.2012-4257. Epub 2013 May 2.
Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL.
The aim of this study was to identify novel disease causing genes in PCC and PGL tumors.
DESIGN, SETTING, AND PARTICIPANTS: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions.
Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007).
We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.
多达 60%的嗜铬细胞瘤（PCC）和副神经节瘤（PGL）与已确定的 PCC 和 PGL 易感性基因座中的体细胞或种系突变有关。大多数无法解释的病例的特征是 RAS/RAF/ERK 信号通路活性增加。RAS 亚型 H、K 和 N 的突变在人类癌症中很常见；然而，以前的研究对于 PCC 和 PGL 中 RAS 的突变状态一直存在不一致。
本研究旨在鉴定 PCC 和 PGL 肿瘤中的新的致病基因。
设计、设置和参与者：对 4 例良性和散发性 PCC 和 PGL 肿瘤进行了全外显子组测序，使用 Illumina HiSeq 平台。使用 CLC Genomics 4.9 生物信息学软件处理序列，并根据癌症体细胞突变目录数据库对获得的遗传变异列表进行过滤。在另外 78 例 PCC 和 PGL 肿瘤病变中验证了这些发现。
外显子组测序鉴定出 2 例 H-RAS 体细胞突变。总共，在主要 PCC 和 PGL 基因座无突变的 6.9%（n = 4/58）肿瘤中有 H-RAS 突变：G13R、Q61K 和 Q61R。有 3 例 PCC 和 1 例 PGL；所有肿瘤均为散发性表现，具有良性肿瘤特征，且去甲肾上腺素和/或肾上腺素显著增加。H-RAS 肿瘤仅在男性患者中发现（P =.007）。
我们在嗜铬细胞瘤和副神经节瘤中发现了复发性 H-RAS 体细胞突变。具有 H-RAS 突变的肿瘤激活了 RAS/RAF/ERK 信号通路，与男性 PCC 患者具有良性和散发性疾病特征有关。H-RAS 可作为预后和预测标志物以及新的治疗靶点。
