Huss Sebastian, Pasternack Helen, Ihle Michaela Angelika, Merkelbach-Bruse Sabine, Heitkötter Birthe, Hartmann Wolfgang, Trautmann Marcel, Gevensleben Heidrun, Büttner Reinhard, Schildhaus Hans-Ulrich, Wardelmann Eva
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Hum Pathol. 2017 Apr;62:206-214. doi: 10.1016/j.humpath.2017.01.005. Epub 2017 Feb 1.
In KIT/PDGFRA wild-type gastrointestinal stromal tumors (wt-GISTs), BRAF mutations are regarded as alternative pathogenic events driving tumorigenesis. In our study, we aimed at analyzing a large cohort (n=444) of GISTs for BRAF mutations using molecular and immunohistochemical methods. More than 3000 GIST samples from caucasian patients were available in our GIST and Sarcoma Registry NRW. Of these, we selected 172 wt-GISTs to evaluate the frequency of BRAF mutations. Furthermore, 272 GISTs with a representative KIT and PDGFRA mutational status were selected. BRAF mutational status was evaluated by high-resolution melting analysis, Sanger sequencing, and VE1 immunohistochemistry. A BRAF mutation (p.V600E) was found in 7 cases (3.9%) of the wt-GIST cohort. In 2 cases, multiple synchronous tumors harbored the same somatic BRAF mutation. VE1 immunohistochemical staining had a sensitivity of 81.8% and a specificity of 97.5% to detect BRAF p.V600E mutations. Analyzing our cases and the cases reported in the literature (n=37), the percentage of intermediate and high-risk BRAF-mutated wt-GISTs (17/31; 54.8%) was comparable to that recorded for large GIST cohorts irrespective of the mutational status. BRAF mutations are rare events in wt-GISTs, and VE1 immunohistochemistry appears to be a valuable pre-screening tool for the detection of BRAF p.V600E mutations. BRAF mutations in GISTs do not seem to have a prognostic value per se. However, as BRAF inhibition represents a therapeutic option to control disease, we suggest the assessment of the BRAF mutational status, especially in the setting of advanced GIST disease.
在KIT/PDGFRA野生型胃肠道间质瘤（wt-GISTs）中，BRAF突变被视为驱动肿瘤发生的替代致病事件。在我们的研究中，我们旨在使用分子和免疫组化方法分析一大组（n=444）GISTs中的BRAF突变情况。我们的北莱茵-威斯特法伦州GIST和肉瘤登记处有来自白种人患者的3000多个GIST样本。其中，我们选择了172个wt-GISTs来评估BRAF突变的频率。此外，还选择了272个具有代表性的KIT和PDGFRA突变状态的GISTs。通过高分辨率熔解分析、桑格测序和VE1免疫组化评估BRAF突变状态。在wt-GIST队列的7例（3.9%）病例中发现了BRAF突变（p.V600E）。在2例中，多个同步肿瘤具有相同的体细胞BRAF突变。VE1免疫组化染色检测BRAF p.V600E突变的敏感性为81.8%，特异性为97.5%。分析我们的病例以及文献报道的病例（n=37），BRAF突变的中高危wt-GISTs的百分比（17/31；54.8%）与大型GIST队列中记录的百分比相当，无论其突变状态如何。BRAF突变在wt-GISTs中是罕见事件，VE1免疫组化似乎是检测BRAF p.V600E突变的有价值的预筛查工具。GISTs中的BRAF突变本身似乎没有预后价值。然而，由于BRAF抑制代表了一种控制疾病的治疗选择，我们建议评估BRAF突变状态，尤其是在晚期GIST疾病的情况下。
