Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
Am J Surg Pathol. 2013 Feb;37(2):234-40. doi: 10.1097/PAS.0b013e3182671178.
A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.
胃胃肠道间质瘤（GIST）的一个亚组（7%-10%）具有免疫组织化学失活琥珀酸脱氢酶（SDH）亚基 B（SDHB）的特征，这表明由线粒体内膜蛋白组成的 SDH 复合物丧失功能。这些 SDH 缺陷型 GIST 已知是 KIT/PDGFRA 野生型，受这种 GIST 亚组影响的大多数患者都很年轻。这些患者中的一些存在 SDH 亚基基因 SDHB、SDHC 或 SDHD 的种系突变，当与副神经节瘤结合时称为 Carney-Stratakis 综合征。最近，在少数 KIT/PDGFRA 野生型 GIST 患者中也报道了 SDH 亚基 A 基因（SDHA）的种系突变。在这项研究中，我们使用鼠单克隆抗体 2E3（Abcam）对 127 例 SDHB 阴性和 556 例 SDHB 阳性胃 GIST 和 261 例 SDHB 阳性肠 GIST 进行了 SDHA 表达的免疫组织化学检查。对有可用 DNA 的病例使用基于杂交的定制捕获下一代测序检测 SDHA、SDHB、SDHC 和 SDHD 基因突变。在 127 例 SDHB 阴性胃 GIST 中发现了 36 例 SDHA 阴性 GIST（28%）。没有 SDHB 阳性 GIST 是 SDHA 阴性的。在分析的 7 例 SDHA 阴性肿瘤中，有 7 例是 SDHA 突变体，大多数是种系突变。在这些病例中，存在第二个提示 SDHA 双等位基因失活的信号。这些患者没有其他 SDH 亚基基因突变。在分析的 25 例 SDHA 阳性、SDHB 阴性 GIST 中，我们鉴定出 3 例 SDHA 突变（1 种为种系突变）和 11 例 SDHB、SDHC 或 SDHD 突变（大多数为种系突变），11 例患者无 SDH 突变。与 SDHA 阳性 GIST 患者相比，SDHA 阴性 GIST 患者的中位年龄较大（34 岁比 21 岁），女性与男性的比例较低（1.8 比 3.1），但有相似的有丝分裂计数和中位肿瘤大小，大多数患者疾病进展缓慢，尽管肝转移的发生率略高。SDHA 阴性 GIST 约占 SDHB 阴性/SDH 缺陷型 GIST 的 30%，SDHA 缺失通常与 SDHA 突变相关。
