SDHA 突变在成人和儿童野生型胃肠道间质瘤中的作用。

SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors.

机构信息

Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands.

出版信息

Mod Pathol. 2013 Mar;26(3):456-63. doi: 10.1038/modpathol.2012.186. Epub 2012 Nov 23.

Abstract

Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.

摘要

大多数胃肠道间质瘤(GIST)存在 KIT 或血小板衍生生长因子受体-α的致癌突变。然而,一小部分 GIST 缺乏这种突变,被称为“野生型 GIST”。琥珀酸脱氢酶(SDH)任何亚基的种系突变使个体易患遗传性副神经节瘤和嗜铬细胞瘤。然而,编码 SDH 亚基 A、B、C 或 D(SDHA、SDHB、SDHC 或 SDHD;统称为 SDHx)的基因的种系突变也在 GIST 中被发现。SDHA 和 SDHB 的免疫组织化学是识别具有 SDHA、SDHB、SDHC 和 SDHD 突变的嗜铬细胞瘤和副神经节瘤的可靠技术。在这项研究中,我们研究了 SDHA 免疫组织化学是否也可以识别 SDHA 突变的 GIST。分析了 24 例成人野生型 GIST 和 9 例儿科/青少年野生型 GIST 的 SDHB,在 SDHB 阴性的情况下,再进行 SDHA 免疫组织化学分析。如果 SDHA 免疫组织化学为阴性,则对整个 SDHA 编码序列进行测序分析。所有 9 例儿科/青少年 GIST 和 7 例成人野生型 GIST 的 SDHB 免疫组织化学均为阴性。1 例儿科 GIST 和 3 例 SDHB 阴性的成人野生型 GIST 的 SDHA 免疫组织化学为阴性。在所有 4 例 SDHA 阴性的 GIST 中,均发现了 SDHA 种系 c.91C>T 转换,导致无意义的 p.Arg31X 突变。我们的结果表明,SDHA 免疫组织化学可用于识别 GIST 中 SDHA 种系突变的存在。鉴定 SDH 活性缺陷的 GIST 需要进行额外的遗传测试、评估和随访,以确定遗传性疾病和副神经节瘤的存在。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索