复发性KIT突变型胃肠道间质瘤（GIST）中一种新型PDGFRA耐药突变的发生

Background: GISTs are sarcomas of the gastrointestinal tract that classically arise through mutations in KIT or PDGFRA tyrosine kinases. GISTs can exhibit both temporal and spatial mutational tumor heterogeneity, however, KIT and PDGFRA mutations are traditionally considered mutually exclusive. To date, only one other case of concurrent mutations exists in the literature. The purpose of this study was to investigate the relationship between primary, metastatic, and recurrent GIST tumors on the genomic level. Methods: This patient with histologically confirmed GIST was enrolled on NCT04557969 and underwent complete cytoreductive surgery for metastatic GIST. A tissue section of the primary tumor was sent for next-generation sequencing (NGS) via the National Cancer Institute Comprehensive Oncologic Molecular Pathology and Sequencing Service (NCI-COMPASS) that utilized the TruSight Oncology 500 Gene Panel for detection of somatic mutations. NGS was repeated upon tumor recurrence and a peri-sigmoid mesocolic metastasis from the index surgery that was retrospectively noted to have no treatment effect. A detailed chart review, including medical history, operative reports, pathology reports, and NGS was performed. Results: This patient is a 51-year-old male who presented with 3 large intra-abdominal masses and was discovered to have a KIT exon 11 GIST on biopsy. He was initiated on imatinib with significant response over one year of therapy. He then underwent exploratory laparotomy with resection of jejunal primary and multiple peritoneal metastases in November, 2023. NGS of the jejunal primary confirmed previously identified KIT exon 11 (p.Val560Asp) mutation. After 1 year of surveillance imaging on adjuvant imatinib, he was found to have an isolated lesion posterior to the left lower rectus. A review of the pathology report from the index surgery identified a peri-sigmoid metastases that demonstrated no treatment effect. A sample of this metastasis was sent for NGS which showed the previously known KIT exon 11 (p.Val560Asp) mutation and a new pathologic structural copy number variation (CNV) loss of CDKN2A on chr9:21968226. He underwent resection of the recurrent mass in March, 2025. NGS of the recurrence demonstrated the KIT exon 11 (p.Val560Asp) mutation, the CNV loss of CDKN2A , and a novel PDGFRA D842Y (p. Asp842Tyr) mutation that is considered imatinib-resistant. Conclusion: This case demonstrates a rare example of a PDGFRA mutation present in a tumor recurrence that arose as a resistance mutation to a baseline KIT mutation. The presence of this CNV loss in both an imatinib -resistant metastasis and the peritoneal recurrence suggests a clonal relationship. This case highlights the geographic and temporal heterogeneity of GIST and underscores the importance of repeat NGS to evaluate GIST recurrences to inform subsequent medical therapy.