Kugelberg Johan, Welander Jenny, Schiavi Francesca, Fassina Ambrogio, Bäckdahl Martin, Larsson Catharina, Opocher Giuseppe, Söderkvist Peter, Dahia Patricia L, Neumann Hartmut P H, Gimm Oliver
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
World J Surg. 2014 Mar;38(3):724-32. doi: 10.1007/s00268-013-2373-2.
Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs.
Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted.
LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.
嗜铬细胞瘤（PCC）起源于肾上腺髓质，通常是遗传性综合征（如冯·希佩尔-林道（VHL）综合征）的一部分。在VHL综合征中，只有约30%携带VHL错义突变的患者会发生PCC。因此，人们在寻找导致VHL综合征患者发生此类肿瘤的其他遗传事件。SDHAF2（以前称为SDH5）和SDHD都位于11号染色体q臂上，是线粒体复合物II功能所必需的。虽然已证明SDHAF2在副神经节瘤（PGL）患者中发生突变，但在PCC患者和PGL患者中均发现了SDHD突变。
由于11号染色体q臂缺失是VHL相关PCC中的常见事件，我们旨在研究SDHAF2和SDHD是否为靶点。在本研究中，对41例VHL相关PCC进行了SDHAF2或SDHD突变及杂合性缺失（LOH）筛查。研究了启动子甲基化以及SDHAF2和SDHD的mRNA表达。此外，对已知为SDH复合物任何部分缺失的通用标志物SDHB进行了免疫组织化学（IHC）检测。
在超过50%的VHL相关PCC中发现了LOH，并且与SDHAF2和SDHD mRNA表达的显著降低（p<0.05）相关，这可能提示其致病作用。然而，虽然在一小部分肿瘤中通过IHC测定的SDHB蛋白表达在PCC中低于周围肾上腺皮质，但与LOH或SDHAF2/SDHD mRNA表达水平没有明显相关性。此外，所研究样本中缺乏突变和启动子甲基化表明11号染色体上的其他事件可能与VHL综合征相关PCC的发生有关。
