Huss Sebastian, Elges Sandra, Trautmann Marcel, Sperveslage Jan, Hartmann Wolfgang, Wardelmann Eva
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Building D17, Albert-Schweitzer-Campus 1, Münster 48149, Germany.
Expert Rev Anticancer Ther. 2015 Jun;15(6):623-8. doi: 10.1586/14737140.2015.1032941. Epub 2015 Apr 1.
Gastrointestinal stromal tumors (GIST) are driven mostly by oncogenic KIT or PDGFRA mutations. However, in 10-15% of all GIST, no such activating mutations can be found and these tumors are classified as 'wild-type GIST' (KIT/PDGFRA wt-GIST). Subgroups of KIT/PDGFRA wt-GIST are driven by other sporadic mutations involving the RAS/RAF/MAP-kinase pathway, such as BRAF or KRAS mutations. Furthermore, KIT/PDGFRA wt-GIST are observed in the context of hereditary syndromes, such as neurofibromatosis Type 1, in which the lack of neurofibromin 1 also leads to the activation of the RAS/RAF/MAP-kinase pathway. Finally, the deficiency succinate dehydrogenase seems to play a major role in KIT/PDGFRA wt-GIST. In conclusion, KIT/PDGFRA wt-GIST belong to different subgroups defined by diverse underlying genetic alterations leading to different biological phenotypes. The vast majority of KIT/PDGFRA wt-GIST will not respond to imatinib. Further research to unravel the pathogenesis of KIT/PDGFRA wt-GIST is prerequisite to the development of effective treatment strategies.
胃肠道间质瘤（GIST）主要由致癌性KIT或PDGFRA突变驱动。然而，在所有GIST中，有10%-15%找不到此类激活突变，这些肿瘤被归类为“野生型GIST”（KIT/PDGFRA野生型GIST）。KIT/PDGFRA野生型GIST的亚组由涉及RAS/RAF/MAP激酶途径的其他散发性突变驱动，如BRAF或KRAS突变。此外，在遗传性综合征（如1型神经纤维瘤病）的背景下可观察到KIT/PDGFRA野生型GIST，其中神经纤维瘤蛋白1的缺乏也会导致RAS/RAF/MAP激酶途径的激活。最后，琥珀酸脱氢酶缺乏似乎在KIT/PDGFRA野生型GIST中起主要作用。总之，KIT/PDGFRA野生型GIST属于不同的亚组，这些亚组由导致不同生物学表型的多种潜在基因改变所定义。绝大多数KIT/PDGFRA野生型GIST对伊马替尼无反应。进一步研究以阐明KIT/PDGFRA野生型GIST的发病机制是制定有效治疗策略的前提条件。
