Molecular characterization and pathogenesis of gastrointestinal stromal tumor

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Most gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine kinase genes, KIT or PDGFRA.
• These mutations activate downstream signaling pathways crucial for GIST development.
• While less common, mutations in RAS pathway genes and NF1 are also implicated in GISTs.

Purpose of the Study:

• To review the molecular landscape of GISTs, focusing on genetic alterations and their impact.
• To discuss the role of succinate dehydrogenase (SDH) gene mutations and epigenetic factors in GIST pathogenesis.
• To define true wild-type GISTs and outline the molecular events in GIST progression.

Main Methods:

• Literature review of studies on GIST genetics and molecular pathology.
• Analysis of mutation data from GIST patient cohorts.
• Review of research on epigenetic alterations and noncoding RNAs in GISTs.

Main Results:

• KIT and PDGFRA mutations are the primary drivers in most GISTs, influencing clinical behavior and drug response.
• Mutations in RAS pathway genes, NF1, and SDH family genes are found in a subset of GISTs, including wild-type cases.
• Epigenetic modifications and noncoding RNAs contribute to GIST pathogenesis and progression.

Conclusions:

• Understanding the diverse molecular alterations in GISTs is critical for risk stratification and treatment.
• KIT/PDGFRA mutations are early events, with additional genetic and epigenetic changes driving malignant progression.
• Further research into the role of SDH, NF1, epigenetic factors, and noncoding RNAs will enhance GIST management.