Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, CB2 OQQ, United Kingdom.
Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, CB2 OQQ, United Kingdom.
Sci Rep. 2019 Jul 15;9(1):10244. doi: 10.1038/s41598-019-46124-9.
The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.
琥珀酸脱氢酶（SDH）在柠檬酸循环中发挥作用，功能丧失易导致嗜铬细胞瘤/副神经节瘤（PPGL）、野生型胃肠道间质瘤（wtGIST）和肾细胞癌的发生。SDH 缺陷型肿瘤通常与种系 SDH 亚基基因突变（SDHA/B/C/D）相关，但也可能与 SDHC 基因的表观遗传沉默相关。然而，SDHC 外显子组突变的临床诊断检测尚未广泛应用。本研究旨在探讨在临床实践中检测 SDHC 外显子组突变的适应证和最佳诊断途径。采用焦磷酸测序技术对 32 例石蜡包埋肿瘤（包括 15 例 GIST 和 17 例 PPGL）进行 SDHC 启动子甲基化分析，并与 SDHC 基因表达相关联。在 6 例（18.7%）肿瘤中发现了 SDHC 启动子甲基化。所有 6 例 SDHC 外显子组甲基化病例均表现为 SDH 缺陷型 wtGIST，3/6 例存在多原发肿瘤。未检测到遗传性 SDHC 启动子高甲基化。对 3 例存在 SDHC 外显子组甲基化的 wtGIST 病例的种系 DNA 进行全基因组测序，未发现任何致病序列异常。在此，我们推荐在服务环境中检测 SDHC 外显子组甲基化的诊断工作流程。
