Oudijk Lindsey, de Krijger Ronald R, Rapa Ida, Beuschlein Felix, de Cubas Aguirre A, Dei Tos Angelo P, Dinjens Winand N M, Korpershoek Esther, Mancikova Veronika, Mannelli Massimo, Papotti Mauro, Vatrano Simona, Robledo Mercedes, Volante Marco
Department of Pathology (L.O., R.R.d.K., W.N.M.D., E.K.), Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Oncology (I.R., M.P., S.V., M.V.), University of Turin at San Luigi Hospital, 10043 Orbassano, Turin, Italy; Endocrine Research Unit (F.B), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-81675 Munich, Germany; Hereditary Endocrine Cancer Group (A.A.d.C., V.M., M.R.), Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Department of Pathology and Molecular Genetics (A.P.D.T.), General Hospital, 31100 Treviso, Italy; Department of Clinical Pathophysiology (M.M.), University of Florence, 50121 Florence Italy; and Centre for Biomedical Network Research on Rare Diseases (CIBERER) (M.R.), 28029 Madrid, Spain.
J Clin Endocrinol Metab. 2014 Jul;99(7):E1376-80. doi: 10.1210/jc.2013-3879. Epub 2014 Mar 31.
Somatic or germline mutations in up to 15 disease-causative genes are detectable in up to 50% of patients with pheochromocytoma (PCC) and paraganglioma (PGL). Very recently, somatic H-RAS mutations were identified by exome sequencing in approximately 7% in sporadic PCCs and PGLs, in association with male sex and benign behavior.
To explore the prevalence of RAS mutations in a cohort of 271 PCC and PGL from a European registry and to compare the genotype with clinical and pathological characteristics of potential clinical interest.
Genetic screening for hotspot mutations in H-, N-, and K-RAS genes was performed by means of Sanger sequencing or pyrosequencing methods on tumor DNA in a series of patients with (n = 107) or without (n = 164) germline or somatic PCC/PGL-related gene mutations.
Overall, H-RAS mutations were detected in 5.2% of cases (14/271), which were confined to sporadic PCCs resulting in a prevalence of 10% (14/140) in this cohort. In contrast, no mutations were found in PCC with PCC/PGL-related gene mutations (0/76) or in PGL (0/55) harboring or not mutations in PCC/PGL susceptibility genes. In this large series, H-RAS mutations in PCCs lacked any significant correlation with pathological or basic clinical endpoints.
Somatic H-RAS mutations are restricted to a relevant proportion of sporadic PCC. These findings provide the basis to study potential H-RAS-dependent correlations with long-term outcome data.
高达50%的嗜铬细胞瘤（PCC）和副神经节瘤（PGL）患者中可检测到多达15个致病基因的体细胞或种系突变。最近，通过外显子组测序在大约7%的散发性PCC和PGL中发现了体细胞H-RAS突变，这些突变与男性性别和良性行为有关。
探讨欧洲登记处271例PCC和PGL队列中RAS突变的发生率，并将基因型与潜在临床相关的临床和病理特征进行比较。
采用桑格测序法或焦磷酸测序法，对一系列有（n = 107）或无（n = 164）种系或体细胞PCC/PGL相关基因突变的患者的肿瘤DNA进行H、N和K-RAS基因热点突变的基因筛查。
总体而言，5.2%的病例（14/271）检测到H-RAS突变，这些突变仅限于散发性PCC，在该队列中的患病率为10%（14/140）。相比之下，在具有PCC/PGL相关基因突变的PCC（0/76）或具有或不具有PCC/PGL易感基因突变的PGL（0/55）中未发现突变。在这个大型队列中，PCC中的H-RAS突变与病理或基本临床终点无显著相关性。
体细胞H-RAS突变仅限于一定比例的散发性PCC。这些发现为研究潜在的H-RAS依赖性与长期预后数据的相关性提供了基础。
