Classification of gastrointestinal stromal tumors based on multiple ohmic structures lays the groundwork for precision therapy

A recent study offering a comprehensive view of the genome and transcriptome of gastrointestinal stromal tumors (GISTs) introduced a new molecular classification of these tumors based on multiple omic structures. This research not only categorizes GISTs into specific molecular subtypes but also identifies YLPM1a potential tumor suppressor gene, providing new insights into GIST pathogenesis and laying the groundwork for precision therapy.

Conducted by the Institute for Intelligent Medical Research (IIMR) at BGI Genomics in collaboration with the Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Ren Ji Hospital, Shanghai Jiao Tong University and others, the study was published in Nature communications in November 2024. The findings elucidate the complex nature of GISTs, identifying critical genetic signatures that contribute to different levels of tumor aggressiveness and response to therapy.

GISTs, the most common type of sarcoma, display a fascinating range of aggressiveness. Unlike other sarcomas, GISTs can range from small, benign tumors to highly invasive, metastatic cancers. While many GISTs share common mutations in TOOL BOX or PDGFRAtheir clinical behavior varies considerably. This study sheds light on these differences, revealing genetic signatures that influence how these tumors progress and respond to therapy, offering a roadmap for more targeted therapies.

Complex genomic features of GISTs

A key finding of the study is that GISTs show remarkably low rates of somatic coding mutations—one of the lowest observed among human cancers. However, they accumulate other genomic alterations, including copy number variations (CNVs) and structural variants (SVs), which contribute to their increased aggressiveness.

Changes in genes such as CDKN2A, DEPDC5, RB1and DMD are more common in advanced GISTs, and massive genomic rearrangement events, such as chromosomal rearrangement and storm, contribute to tumor progression by remodeling the genome. These mutations play a critical role in the transformation of GISTs into more invasive forms, highlighting the need for targeted interventions in advanced cases.

Adding another layer of complexity, GISTs exhibit significant genetic heterogeneity, with different mutations occurring at different tumor sites, especially in metastatic cases. This diversity complicates treatment strategies, as treatments such as tyrosine kinase inhibitors (TKIs), commonly used for TOOL BOX-mutant GISTs may become less effective over time as the tumor adapts and develops resistance. Understanding the genetic diversity within an individual’s GIST tumors can help improve treatment plans and explore combination therapies to address resistance.

The study’s transcriptome-based classification reveals four distinct molecular subtypes within GISTs, each with unique genomic and immunological features that can inform treatment strategies. For example, C1, a genome-wide stable subtype consisting primarily of low- to intermediate-risk gastric GISTs with TOOL BOX mutations, generally has a favorable prognosis only with surgical resection. The C2 subtype, defined as CD8+ inflammatory, includes high-risk intestinal GISTs with high infiltration of immune cells, particularly CD8+ T cells, suggesting that these tumors may benefit from a combination of TKI and immunotherapy.

Meanwhile, the C3 subtype, known as the immune desert subtype, represents high-risk gastric GISTs with frequent CDKN2A deletions, showing limited immune activity and possible response to CDK4/6 inhibitors in combination with TKIs. Finally, the C4 subtype includes PDGFRA mutant GISTs, which respond well to PDGFRA inhibitors such as avapritinib, although they remain resistant to standard TKIs.

Novel tumor suppressor gene in GIST

Another important finding of the study is its recognition YLPM1 as a GIST-specific tumor suppressor gene. Although widely expressed in various tissues, YLPM1 appears particularly critical in GISTs, where its inactivation promotes cell proliferation and increases oxidative phosphorylation, fueling tumor growth. On experimental models, reset YLPM1 The function in GIST cells slowed tumor progression, positioning it as a promising target for future therapies. This finding offers new treatment directions, especially in targeting YLPM1-deficient GIST to limit their growth.

This comprehensive multi-omics analysis not only advances our understanding of the molecular profile of GISTs but also bridges the gap between basic research and clinical application. By identifying specific molecular subtypes, the study enables doctors to consider more personalized treatment strategies. For example, patients with C2 tumors may benefit from a combination of TKI and immunotherapy, while those with C3 tumors could explore the synergistic effects of CDK4/6 inhibitors with TKIs.

The study’s findings underscore the importance of understanding the genetic nuances in GISTs and tailoring treatment approaches accordingly. As clinical trials further validate these findings, this molecular taxonomy could revolutionize the way GISTs are managed, bringing us closer to a future of personalized precision medicine for GIST patients.