Quaas Alexander, Heydt Carina, Waldschmidt Dirk, Alakus Hakan, Zander Thomas, Goeser Tobias, Kasper Philipp, Bruns Christiane, Brunn Anna, Roth Wilfried, Hartmann Nils, Bunck Anne, Schmidt Matthias, Buettner Reinhard, Merkelbach-Bruse Sabine
Institute of Pathology, University of Cologne, Cologne, Germany.
Department of Hepato- and Gastroenterology, University of Cologne, Cologne, Germany.
BMC Gastroenterol. 2019 Feb 4;19(1):21. doi: 10.1186/s12876-019-0942-z.
Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.
We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).
In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.
Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.
小肠癌是罕见肿瘤，预后通常较差。最近，有一些潜在可治疗的分子改变被描述。我们强调小肠癌个体化治疗方案的证据越来越多。
我们对11例福尔马林固定石蜡包埋的小肠癌进行了基于DNA的多基因检测，采用超深度测序分析（包括14个基因，共452个扩增子；KRAS、NRAS、HRAS、BRAF、DDR2、ERBB2、KEAP1、NFE2L2、PIK3CA、PTEN、RHOA、BRCA1、BRCA2和TP53）以及基于RNA的基因融合检测，包括ALK、BRAF、FGFR1、FGFR2、FGFR3、MET、NRG1、NTRK1、NTRK2、NTRK3、RET和ROS1。此外，通过使用五个不同的单核苷酸标记BAT25、BAT26、NR - 21、NR - 22和NR - 27检查微卫星状态以及使用四个不同的标记（MLH1、MSH6、MSH2、PMS2）检测错配修复蛋白的缺失来分析错配修复缺陷。
在11例小肠癌中有5例发现了潜在可治疗的基因改变。3例患者表现出致病性（5类）BRCA1或BRCA2突变——其中1例与混合性神经内分泌 - 非神经内分泌肿瘤（MiNEN）相关的种系突变。另外2例患者发现激活的ERBB2突变或PIK3CA突变。此外，2例肿瘤为高度微卫星不稳定（MSI - 高），其中1例与林奇综合征相关。我们未发现任何基因融合。
我们的结果特别强调了小肠癌中潜在可治疗分子改变（如ERBB2、BRCA和MSI）的相关性。需要进一步研究来证实这些靶向治疗在小肠癌中的疗效。
