Genomic, Transcriptomic and Immunogenomic Analysis in Sarcomas and New Therapeutic Targets

🧬 Why Is Understanding a Rare Cancer Type Vital?

Sarcomas are rare cancers that arise from connective tissue and can occur anywhere in the body. Although they account for approximately 1% of all cancers, the existence of more than 100 subtypes makes their diagnosis and treatment particularly challenging.

Because of their genetic and molecular diversity, understanding the fundamental biology of this disease group is critical to developing effective, personalized treatment strategies . Unfortunately, current treatment options for advanced sarcomas are limited and often not curative.

Mapping sarcomas at the molecular level to identify factors affecting the disease course and discover new therapeutic targets is therefore of great scientific and clinical importance.

On May 6, 2025, Nature Communicationspublished a study in which 1340 sarcoma tumor samples underwent whole-exome (WES) and RNA sequencing analyses, which showed that metastatic tumors had a higher mutational burden than primary tumors (p < 0.001).

This increase was attributed particularly to alterations in TP53 (26%) and ATRX (8.9%) , tumor suppressor genes, in the form of inactivating mutations , while no significant change in the frequency of oncogenic driver mutations was observed.

In addition, whole-genome duplication (WGD) was more common in metastatic samples (p = 0.026). This was particularly evident in GISTand suggests that it may play a critical role in this tumor type in terms of secondary mutations and tumor progression.

This comprehensive analysis examined differences in gene expression among sarcoma subtypes in depth. It showed that tumors of the same histological subtype also form genetically similar clusters .

In particular, subtypes such as leiomyosarcoma, GIST, myxoid liposarcoma and dedifferentiated/well-differentiated liposarcoma were found to form distinct expression subgroups. This finding shows that morphological similarities are also reflected at the molecular level.

The table below shows the genes highly expressed in each sarcoma subtype and their biological roles:

Immune groups were classified according to the density of immune cells in the tumor microenvironment , and each group was associated with specific sarcoma subtypes:

Survival analysesshowed that patients in immune cell-rich “hot” groups had longer overall survival than patients in “cold” groups.

In particular, angiosarcoma and undifferentiated pleomorphic sarcoma were among the subtypes known to be sensitive to immunotherapy that were found more frequently in the “hot” groups.

💡 Clinical implication: Profiling the tumor’s immune microenvironment is critical for predicting survival and identifying patients who may benefit from immunotherapy .

This comprehensive study provides important molecular insights into sarcomas, taking their rare and heterogeneous nature into account. Molecular differences between primary and metastatic tumors , when clarified, offer new clues about disease progression and mechanisms of treatment resistance .

🎯 Subtype-Specific Molecular Targets:

🧬 TP53 and ATRX Mutations: These inactivating mutations, particularly common in metastatic tumors, are associated with DNA repair and chromatin structure. In this context, PARP inhibitors or epigenetic regulators may offer potential therapeutic approaches.

Whole-Genome Duplication (WGD): Common in metastatic GISTs, this condition may contribute to genetic heterogeneity and treatment resistance. CHEK1 and ATR inhibitors are among the promising options for this group.

🧪 Immunogenomic Profiling:

• “Hot” immune groups: High T cell density (e.g., angiosarcoma, UPS) → PD-1/PD-L1 inhibitors may provide benefit.
• “Intermediate” immune group (GIST): NK cell enrichment → NK cell activators or dendritic cell vaccines may be suitable approaches.

🔬 Clinical implication: These findings create new opportunities for personalized treatment strategies and show that molecular mapping of sarcomas may guide future treatment protocols.