Clinicopathological features of wild-type GISTs based on multiple-gene panel analysis

Background: Clinicopathological features and prognosis of wild-type GIST defined as GIST lacking mutations in KIT and PDGFRA genes are unknown. We conducted the panel analysis of wild-type GIST. Methods: Cohort 1: Total 255 pts with primary GISTs underwent surgery in 2 hospitals were consecutively registered between 2003 and 2014. Cohort 2: Total 515 pts with high-risk GISTs by Modified NIH classification diagnosed in 127 hospitals were prospectively registered between 2012 and 2015. Median follow-up periods of Cohort 1 and 2 were 3.4 and 4.2 years, respectively. Genotyping was performed using surgical specimens with conventional PCR/sequencing of KIT and PDGFRA, and, then, targeted sequencing with NCC Oncopanel ver. 5 for wild-type GIST. Results: Wild-type GISTs found in Cohort 1 and 2 were 17 (6.7%) and 19 (3.7%), respectively. Compared with KIT-mutated GISTs, wild-type and PDGFRA-mutated GISTs showed lower mitotic counts (p = 0.009) and better recurrent-free survival (p = 0.004) in Cohort 1. Age at diagnosis was significantly younger in wild-type GIST than KIT- and PDGFRA-mutated GISTs. Frequency of high risk GISTs was similar among 3 mutation groups. Total 36 wild-type GISTs from two Cohorts located in the stomach (n = 16), small intestine (18), lower esophagus (1) or extra-GI (1). Panel analysis found mutations in NF1 (13), SDH complex (6; SDHA=3 and SDHB=3), BRAF (5), and no known GIST-associated mutation in 7 (the other 5 were not analytical due to poor or no DNA). BRAF-mutated (4 out of 5) and NF1-GISTs (10 of 13) mainly located in the small intestine, and SDH-mutated (5 of 6) located in the stomach. Multiple GISTs were recognized in 10 pts including 6 (46% of NF1) NF1- and 3 (50%) SDH-mutated GISTs. Among genotypes, there were no difference in tumor size and mitotic counts, but SDH-mutated GISTs were significantly younger than the other wild-type GISTs. Among 13 NF1-GIST pts, only 1 had family history and 5 pts met the diagnostic criteria of NF1. With a median follow-up of 3.4 years, new relpases were found in 10 pts with high risk GISTs. 15 out of 24 high risk wild-type GISTs received adjuvant therapy and 6 pts of 15 had relapses even under imatinib. Conclusions: Wild-type GIST is a heterogeneous disease and relapse was associated with high-risk features despite imatinib-adjuvant. Clinical trial identification: UMIN000009531. Legal entity responsible for the study: STAR Registry Goup. Funding: The National Cancer Center Research and Development Fund. Disclosure: All authors have declared no conflicts of interest.