Table III.
Mutational status, mutation location, allelic frequency, pathogenicity, and clinical benefit to imatinib in KIT/PDGFRA/BRAF WT GIST patients as assessed by standard methods reverse transcription-quantitative PCR and Sanger sequencing.
| n | SDH IHC | Clinically significant gene variants in GIST (NGS) | cDNA variant description | Predicted protein | Pathogenicity ACMG/AMPf | VAF (%) | TMB (mut/MB) ns/(ns+s) | Clinical benefit to imatinib | RECIST evaluation (22) |
|---|---|---|---|---|---|---|---|---|---|
| 1a | Loss | WT | 6/7 | NT | NA | ||||
| 2 | Comp. | WT | 1/2 | No | PD | ||||
| 3b | Comp. | WT | 1/1 | No | PD | ||||
| 4 | Comp. | WT | 0/1 | No | PD | ||||
| 5 | Comp. | WT | 2/3 | No | PD | ||||
| 6b,c | Comp. | NF1 (LRG_214t1) | c.4537C>T | p. (Arg1513*) R1513* | P | 96.27 | 2/2 | Yes | SD |
| 7 | Loss | SDHA (LRG_315t1) | c.776delinsGC | p. (Tyr259Cysfs*62) | LP | 69.66 | 4/4 | No | PD |
| Y259Cfs*62 | |||||||||
| 8 | Loss | SDHB (LRG_316t1) | c.268C>T | p. (Arg90*) R90* | LP | 30.4 | NA | No | PD |
| 9b,d | Loss | SDHB (LRG_316t1) | c.688C>T | p. (Arg230Cys) R230C | LP | 79.31 | 4/4 | NT | NA |
| 10b,g | Comp. | PDGFRA (LRG_309t1) | c.2525A>T | p. (Asp842Val) D584V | P | 41.17 | 0/0 | Yes | CR |
| 11b | Comp. | PDGFRA (LRG_309t1) | c.1682T>A | p. (Val561Asp) V561D | P | 84.61 | 2/3 | Yes | CR |
| 12b | Comp. | PDGFRA (LRG_309t1) | c.1936A>G | p. (Lys646Glu) K646E p. | LP LP | 40.56 | 2/3 | Yes | CR |
| c.1975A>C | (Asn659His) N659H | 41.27 | |||||||
| 13b | Comp. | PDGFRA (LRG_309t1) | c.1679T>A | p. (Val560Asp) V560D | P | 43.35 | 1/1 | Yes | CR |
| 14 | Comp. | KIT (LRG_307t1) | c.1669_1674del | p. (Trp557_Lys558del) | LP | 47.21 | 0/0 | Yes | PR |
| W557_K558del | |||||||||
| 15 | Comp. | KIT (LRG_307t1) | c.1671_1676del | p. (Trp557_Val559delinsCys) | LP | 41.2 | 1/3 | Yes | PR |
| W557_V559delinsC | |||||||||
| 16b | Comp. | KIT (LRG_307t1) | c.1648-3_1673del | p. (Lys550_Lys558del) | LP | 39.9 | 2/2 | Yes | PR |
| K550_K558del | |||||||||
| 17e | NA | NA | NA | NA | NA | NA | NA | No | PD |
WT, wild type; P, pathogenic; LP, likely pathogenic; VAF, variant allele frequency; TMB, tumor mutational burden; ns, nonsynonymous; s, synonymous; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; RECIST, response evaluation criteria in solid tumors; NA, not applicable; NT, not treated; comp., competent;
upfront treated with sunitinib;
besides DNA, also RNA was sequenced by TruSight Tumor 170-RNA;
confirmed germline mutation;
radiofrequency ablation of solitary liver metastasis;
not enough material for additional testing;
Pathogenicity determined according to ACMG/AMP guidelines (58);
resistant mutation PDGFRA D84.2V.