Consensus or Controversy Should Mutational Analysis (Ma) Be Considered as a Routine Testing in the Clinical Management of Gastrointestinal Stromal Tumor (GIST) in the Era of Personalized Medicine?

As with other malignancies, GISTs evolve over time and may develop various types of mutations over the disease trajectory. At diagnosis, it is known that most GISTs, in fact roughly 70-90% of GISTs contain various types of gain of function mutations in KIT (exons 9 (~10%), 11 (~70%), 13(~2%), 17(~1%)) or platelet derived growth factor alpha (PDGFRα) (exons 12 (~1%), 14 (~1%), 18 (~8%)) oncogenes [1]. ~10-15% of GISTs are so called wild-type (wt) GISTs that do not contain KIT/ PDGFRα mutations [1]. About 20-40% of wt GISTs overexpress insulin growth factor 1 receptor (IGF1R) and have loss of expression of the succinate dehydrogenase complex either due to mutations in one of four SDH subunits (SDHA/SDHB/SDHC/SDHD) or promoter hypermethylation of SDHC collectively defined as SDH-deficient GISTs [2]. The rest of wt GISTs may contain alterations affecting the gene for neurofibromatosis 1 (NF1) or genes coding for members of the RAS signaling pathway such as BRAF (~4%)/RAS (<1%)/PIK3CA (<1%) [3]. GISTs that do not contain mutations in KIT/PDGFRα/RAS pathway/SDH mutations are referred as quadruple wt GISTs, likely in the range of ~5% in prevalence [4]. ETV6-NTRK3 and FGFR1-TACC1 translocation are recently identified in quadruple wt GISTs [5-7].