Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The genetic causes of sporadic angiosarcoma are not well understood.
• Maffucci syndrome, linked to IDH1/2 mutations, involves vascular tumors, but these mutations were previously unreported in sporadic angiosarcoma.

Purpose of the Study:

• To investigate the genetic underpinnings of sporadic angiosarcoma.
• To explore the therapeutic potential of targeting IDH1/2 mutations in angiosarcoma.

Main Methods:

• Whole-exome sequencing to identify mutations.
• Sanger sequencing and immunohistochemistry for validation.
• In vitro studies on mutant IDH1 endothelial cells.
• Clinical assessment of ivosidenib treatment response.

Main Results:

• Recurrent, low-variant allele frequency hotspot mutations in IDH1/2 were found in over half of sporadic angiosarcomas.
• Mutant IDH1 promotes tumorigenesis via non-cell-autonomous mechanisms, including 2-hydroxyglutarate secretion.
• Ivosidenib reversed these pro-tumorigenic effects in vitro and led to significant tumor regression in patients.

Conclusions:

• Subclonal IDH1/2 mutations are a significant driver of sporadic angiosarcoma.
• Ivosidenib is a promising targeted therapy for angiosarcomas with low-VAF IDH1/2 mutations.
• Targeting IDH1/2 mutations represents a novel therapeutic vulnerability in vascular tumors.