A RECENT study has developed a new molecular classification for gastrointestinal stromal tumours (GIST) through multi-omics analysis, uncovering four distinct subtypes and identifying a potential tumour suppressor gene, YLPM1, to guide future precision treatments.
Historically, GISTs have shared common mutations, especially in KIT and PDGFRA genes, but their clinical behaviour varies widely. Conducted by BGI Genomics’ Institute of Intelligent Medical Research and collaborators, the research maps out the genomic and transcriptomic landscape of GISTs, the most common sarcoma of the gastrointestinal tract. The study identifies genetic differences underlying the varied behaviour of GISTs, from benign tumours to aggressive, metastatic cancers.
The researchers analysed the genomes of GIST samples, observing low rates of typical somatic mutations but a high incidence of complex genomic alterations, such as copy number variations and structural rearrangements, like chromothripsis. Advanced GISTs frequently displayed alterations in genes CDKN2A, DEPDC5, RB1, and DMD, revealing how genomic instability contributes to GIST progression.
The study also introduced a four-subtype classification based on transcriptome data: the genome-stable C1 subtype, inflamed C2 subtype, immune-desert C3 subtype, and PDGFRA-mutant C4 subtype. These subtypes have distinct molecular and immune profiles; for instance, C2 tumours, with high CD8+ T-cell infiltration, may benefit from combined tyrosine kinase inhibitors and immunotherapy, while C3 tumours with CDKN2A deletions could respond to CDK4/6 inhibitors.
One of the most promising discoveries is the identification of YLPM1 as a tumour suppressor gene specifically relevant to GISTs. Inactivation of YLPM1 drives tumour growth, while restoring its function in models slowed tumour progression, suggesting it as a new therapeutic target.
This study’s insights into the molecular profiles of GISTs pave the way for tailored treatments, encouraging a shift from standard therapies to personalised strategies. Future clinical trials could help validate these findings.
Reference
Xie F et al. Genomic and transcriptomic landscape of human gastrointestinal stromal tumors. Nat Commun. 2024;15(1):9495.
