Wild-Type Gastrointestinal Stromal Tumors—Molecular Features, Frequency, and Consequences Among the Indian Population

Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or PDGFRA receptors rendering resistance to tyrosine kinase receptor inhibitors, such as imatinib. Among these WT-GISTs, a small subset is associated with loss of function of succinate dehydrogenase (SDH). It is postulated that SDH deficiency leads to activation of insulin-like growth factor 1-receptor (IGF1R) signaling which in turn results in oncogenesis. SDH-proficient WT-GISTs on the other hand are associated with other mutations such as Neurofibromatosis type-1 (NF1), BRAF, and RAS. The study compared the overall survival among the SDH-deficient vs. SDH-proficient WT-GIST groups. In the present study, 265 histologically confirmed cases of GIST accessioned over the period of 2014–2018 were analyzed for KIT, PDGFRA gene mutations by sequencing on the ABI 3500 Gene Analyzer (Applied Biosystems, Foster City, USA), and BRAFV600 gene mutation using the real-time (RT) PCR assay on ABI™ Quant Studio 12K Flex System. SDH protein expression was evaluated by immunohistochemistry using the mouse monoclonal antibody against SDHB (clone 21A11AE7; Abcam, Cambridge, MA). WT-GIST cases constituted 12.3% of the total GIST cases (30/243). Based on SDH expression, 9 cases (30%) were SDH-deficient and 18 cases (60%) were SDH-proficient. The overall survival rate of the SDH-proficient group was 67.3%, whereas the SDH-deficient group had a 100% survival rate during the study period. WT-GIST although rare is a unique entity which needs molecular characterization for better clinical management of the patients. The SDH-deficient WT-GIST group was associated with a better clinical outcome, thereby suggesting the importance of recognizing these patients in clinical practice.