Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Genes Chromosomes Cancer. 2022 Jul;61(7):412-419. doi: 10.1002/gcc.23030. Epub 2022 Feb 22.
Genetic alterations in FGF/FGFR pathway are infrequent in gastrointestinal stromal tumors (GIST), with rare cases of quadruple wildtype GISTs harboring FGFR1 gene fusions and mutations. Additionally, FGF/FGFR overexpression was shown to promote drug resistance to kinase inhibitors in GISTs. However, FGFR gene fusions have not been directly implicated as a mechanism of drug resistance in GISTs. Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib-sensitive KIT exon 11 in-frame deletion. After an initial 9-month benefit to imatinib, the patient experienced intraabdominal peritoneal recurrence owing to secondary KIT exon 13 missense mutation and FGFR4 amplification. Despite several additional rounds of tyrosine kinase inhibitors (TKI), the patient's disease progressed after 2 years and presented with multiple peritoneal and liver metastases, including one pericolonic mass harboring secondary KIT exon 18 missense mutation, and a concurrent transverse colonic mass with a FGFR2::TACC2 fusion and AKT2 amplification. All tumors, including primary and recurrent masses, harbored an MGA c.7272 T > G (p.Y2424*) nonsense mutation and CDKN2A/CDKN2B/MTAP deletions. The transcolonic mass showed elevated mitotic count (18/10 HPF), as well as significant decrease in CD117 and DOG1 expression, in contrast to all the other resistant nodules that displayed diffuse and strong CD117 and DOG1 immunostaining. The FGFR2::TACC2 fusion resulted from a 742 kb intrachromosomal inversion at the chr10q26.3 locus, leading to a fusion between exons 1-17 of FGFR2 and exons 7-17 TACC2, which preserves the extracellular and protein tyrosine kinase domains of FGFR2. We present the first report of a multidrug-resistant GIST patient who developed an FGFR2 gene fusion as a secondary genetic event to the selective pressure of various TKIs. This case also highlights the heterogeneous escape mechanisms to targeted therapy across various tumor nodules, spanning from both KIT-dependent and KIT-independent off-target activation pathways.
成纤维细胞生长因子/成纤维细胞生长因子受体（FGF/FGFR）通路中的基因改变在胃肠道间质瘤（GIST）中并不常见，罕见的四重野生型 GIST 存在 FGFR1 基因融合和突变。此外，FGF/FGFR 过表达被证明可促进 GIST 对激酶抑制剂的耐药性。然而，FGFR 基因融合尚未被直接牵连为 GIST 耐药的机制。在此，我们报告了一名患有原发性小肠梭形细胞 GIST 并伴有腹膜和肝脏转移的患者，其 KIT 外显子 11 存在伊马替尼敏感的框内缺失。在最初 9 个月的伊马替尼治疗中获益后，由于继发的 KIT 外显子 13 错义突变和 FGFR4 扩增，患者出现了腹腔内腹膜复发。尽管进行了几轮酪氨酸激酶抑制剂（TKI）治疗，但在 2 年后，患者的疾病进展，并出现了多个腹膜和肝脏转移，包括一个继发的 KIT 外显子 18 错义突变的结肠旁肿块，以及一个同时存在的横结肠肿块，该肿块具有 FGFR2::TACC2 融合和 AKT2 扩增。所有肿瘤，包括原发和复发性肿块，均存在 MGA c.7272 T > G（p.Y2424*）无义突变和 CDKN2A/CDKN2B/MTAP 缺失。与所有显示弥漫性和强 CD117 和 DOG1 免疫染色的其他耐药结节相比，横结肠肿块显示出较高的有丝分裂计数（18/10 HPF），以及 CD117 和 DOG1 表达的显著降低。FGFR2::TACC2 融合是由于 chr10q26.3 位点的 742 kb 染色体内倒位导致的，导致 FGFR2 的外显子 1-17 与 TACC2 的外显子 7-17 融合，保留了 FGFR2 的细胞外和蛋白酪氨酸激酶结构域。我们报告了首例多药耐药 GIST 患者的病例，该患者在各种 TKI 的选择性压力下发生了 FGFR2 基因融合作为继发的遗传事件。该病例还突出了靶向治疗中不同肿瘤结节的异质逃逸机制，涵盖了 KIT 依赖性和 KIT 非依赖性的非靶标激活途径。
