Genomic profiling in GIST: Implications in clinical outcome and future challenges

Abstract

Gastrointestinal Stromal Tumors (GIST) are the most frequent mesenchymal neoplasia of the digestive tract. Genomic alterations in KIT, PDFGRA, SDH, and BRAF genes are essential in GIST oncogenesis. Therefore, the mutations in these genes have demonstrated clinical implications. Tumors with deletions in KIT-exon 11 or duplications in exon 9 are associated with a worse prognosis. In contrast, KIT-exon 11 substitutions and duplications are associated with a better clinical outcome. Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. Although, molecular testing on tissue samples is effective; it is invasive, requires adequate amounts of tissue, and a long experimental process is needed for results. In contrast, liquid biopsy has been proposed as a simple and non-invasive method to test biomarkers in cancer. The most common molecule analyzed by liquid biopsy is circulating tumor DNA (ctDNA). GISTs ctDNA testing has been demonstrated to be effective in identifying known and novel KIT mutations that were not detected using traditional tissue DNA testing and have been useful in determining progression risk and response to TKI therapy. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

Keywords: GIST; Genomic profiling; KIT; Mutations; PDGFRA; Treatment.

Fig. 1

Molecular landscape in GIST is related to treatment response. (A) principal signaling pathways involved in GIST development and progression. The hyperactivity of tyrosine kinase receptors triggers Jack/Stat, K-ras/MAPK and NF-1 signaling pathways to induce cell proliferation. (B) Drug response of GIST tumors is related to KIT or PDGFRA gene mutations. Tyrosine kinase inhibitors are directed to alterations in cytoplasmic domain of the codified-receptors. Color circles represent sensitivity (green) or resistance (red) to the respective pharmacologic agent.

Fig. 2

Liquid biopsy implications in genomic profiling of GIST. The utility of liquid biopsy in diagnosis and monitoring of GIST is schematized. Liquid biopsy is one of the most useful techniques to determine molecular profiling, define the optimal choice of therapy, and predict response to treatment based on resistance mutations, representing a master key in the era of personalized medicine.