Urbini Milena, Astolfi Annalisa, Indio Valentina, Heinrich Michael C, Corless Christopher L, Nannini Margherita, Ravegnini Gloria, Biasco Guido, Pantaleo Maria A
"Giorgio Prodi" Cancer Research Center, University of Bologna, via Massarenti 11, 40138, Bologna, Italy.
VA Portland Health Care System and OHSU Knight Cancer Institute, and Division of Hematology and Oncology, Oregon Health & Science University, Portland, Oregon, USA.
BMC Med Genet. 2015 Sep 28;16:87. doi: 10.1186/s12881-015-0233-7.
Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type. Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST.
We report a particular case of dSDH GIST, previously analyzed with microarrays and next-generation sequencing, for which no molecular pathogenetic events have been identified. Gene expression analysis showed remarkable down-modulation of SDHC mRNA with respect to all other GIST samples, both SDHA-mutant and KIT/PDGFRA-mutant GIST. By a bisulfite methylation assay targeted to 2 SDHC CpG islands, we detected hypermethylation of the SDHC promoter.
Herein we report an additional case of dSDH GIST without SDHx mutation but harboring hypermethylation in the SDHC promoter, thus confirming the complexity of the molecular background of this subtype of GIST.
胃肠道间质瘤（GIST）最近被认为是一种基因和生物学上异质性的疾病。除了KIT或PDGFRA突变的GIST外，在KIT/PDGFRA野生型亚组中检测到琥珀酸脱氢酶（SDH）亚基的突变失活，称为SDH缺陷型（dSDH）。尽管大多数dSDH GIST在SDHx亚基基因中存在突变，但有些是SDHx野生型。最近发现，CpG岛的DNA甲基化引起的表观遗传调控是GIST中SDH复合物缺乏的另一种潜在机制。
我们报告了一例特殊的dSDH GIST病例，此前已用微阵列和下一代测序进行分析，未发现分子致病事件。基因表达分析显示，相对于所有其他GIST样本，包括SDHA突变型和KIT/PDGFRA突变型GIST，SDHC mRNA均有显著下调。通过针对2个SDHC CpG岛的亚硫酸氢盐甲基化检测，我们检测到SDHC启动子的高甲基化。
在此，我们报告了另一例dSDH GIST病例，该病例无SDHx突变，但SDHC启动子存在高甲基化，从而证实了这种GIST亚型分子背景的复杂性。
