Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Adv Anat Pathol. 2017 Sep;24(5):259-267. doi: 10.1097/PAP.0000000000000158.
The classification "gastrointestinal stromal tumor" (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (microGIST) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis.
“胃肠道间质瘤”（GIST）的分类在 20 世纪 90 年代变得很普遍，自那时以来，GIST 的起源、酪氨酸激酶突变以及对靶向治疗的反应和耐药机制的各种进展已经得到了描述。除了酪氨酸激酶突变及其下游信号通路的组成性激活外，GIST 还获得了一系列染色体异常。这些异常包括染色体 14q、22q、1p 和 15q 的缺失，这些染色体携带着逐步进展所需的潜在肿瘤抑制基因，从微观、临床前形式的 GIST（microGIST）到具有恶性潜能的临床相关肿瘤。最近的进展扩展了我们对 GIST 生物学的理解，超越了致癌 KIT/PDGFRA 酪氨酸激酶及其 KIT/PDGFRA 抑制剂治疗反应和耐药机制的理解。这些进展将 ETV1 确定为致癌 KIT 信号通路中 Cajal-GIST 转录因子的必需间质细胞，并确定了生物上不同的琥珀酸脱氢酶缺乏型 GIST 亚组，该亚组在年轻人中特别常见。此外，最近发现 MAX 和肌营养不良蛋白基因组失活扩展了我们对 GIST 发生和进展的理解，表明 MAX 失活是促进细胞周期活性的早期事件，而肌营养不良蛋白失活则促进侵袭和转移。
