Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor.
In subsets of gastrointestinal stromal tumors (GISTs), mutations of the KIT and PDGFRA receptor tyrosine kinases correlate with tumor prognosis and response to tyrosine kinase inhibitors (TKIs). Determining genotypes in TKI-resistant GISTs is challenging due to the potential risks and limitations of repeated biopsies during the course of treatment. We prospectively collected plasma samples from three GIST patients harboring KIT mutations that were detected in tissue DNA. The plasma samples were then analyzed for mutations in KIT, PDGFRA, and BRAF via next-generation sequencing. We were able to identify primary KIT mutations in all plasma samples. Additional mutations, including KIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TKIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST. These mutations can be used as biomarkers for prediction of treatment response. The identification of a resistance mutation in plasma DNA will allow early change to alternative TKIs or dose escalation of imatinib for optimal patient management.
Department of Pathology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea.
Guhyun
G
Kang
Department of Surgery, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea.
Byung Noe
BN
Bae
Department of Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea.
Byeong Seok
BS
Sohn
Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Jung-Soo
JS
Pyo
Department of Medicine, Chungnam National University Hospital, Daejeon, South Korea.
Gu Hyum
GH
Kang
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, 135-710, South Korea. kkmkys@skku.edu.
Kyoung-Mee
KM
Kim
D000369:Aged, 80 and over; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
Circulating tumor DNA; Gastrointestinal stromal tumor; Next-generation sequencing; Resistance mutation; Tyrosine kinase inhibitor